Conditions: Chronic Lymphocytic Leukemia CLL SLL Small Lymphocytic Lymphoma
Keywords: Tolero Phase 1/2 First in human Previously treated Chronic Lymphocytic Leukemia (CLL) Previously treated Small Lymphocytic Lymphoma (SLL) AXL inhibitor Cancer Advanced Cancer Relapsed / Refractory CLL
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
TP-0903 is an inhibitor of AXL kinase. TP-0903 has shown potent inhibition of AXL kinase and other TAM family members in a biochemical kinase assay. TP-0903 demonstrates corresponding activity in cancer cell lines and mouse xenograft efficacy models. TP-0903 is shown to block cancer cell epithelial-to-mesenchymal transitions. AXL was identified as a potential therapeutic target in chronic lymphocytic leukemia (CLL). TP 0903 was shown to induce apoptosis in CLL B-cells taken directly from patients.TP-0903 was equally potent against CLL cells regardless of risk-factor.

TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. TP-0903 has demonstrated profound single agent activity in CLL B cells taken directly from patients even if the patient has high risk factors (ie, 17p/P53 deletions) or progressed on other agents (ie, ibrutinib). TP-0903 is currently being evaluated in patients with refractory solid tumors (TP-0903-101). This proposed study is designed to identify the maximum tolerated dose (MTD), safety profile and recommended Phase 2 dose (RP2D) of TP-0903 in patients with previously treated CLL. Treatment cycles may be repeated if the patient continues to show benefit and if TP-0903 is reasonably well tolerated.

The study will investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TP-0903.

Detailed description:
This is a combined Phase 1/2 study of oral TP-0903 in patients with previously treated CLL/SLL. In both Phase 1 and Phase 2, study participants will be assigned to one of two defined patient groups:

* Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who are intolerant to, or have progressed on, B-cell receptor antagonists and/or BCL-2 antagonists
* Group 2 (TP-0903 and ibrutinib combination therapy): Patients with CLL/SLL who have progressed on ibrutinib yet the treating provider considers continuation of ibrutinib therapy to be in the best interest of the patient.

Both groups of patients will be treated identically with TP 0903 and will undergo the same study assessments.

Phase 1 Patients will be enrolled in Group 1 and Group 2 in cohorts of 3 to 6 patients simultaneously. Group 2 will start at one dose level below the Group 1 starting dose. In each group, escalation of the TP-0903 dose will follow a standard 3+3 design with sequential cohorts of three patients treated with incrementally higher doses of TP 0903 until a dose-limiting toxicity (DLT) is observed and the maximum tolerated dose (MTD) is established. In the absence of DLTs, the dose will be increased using a modified Fibonacci dose escalation scheme.

Once the MTD or preliminary RP2D is identified, an expansion cohort of up to 6 patients will be enrolled in each patient group to confirm safety/suitability of the preliminary RP2D, to collect additional biomarker data, and to further explore efficacy.

It is expected that up to 27 patients will be enrolled in each patient group for a total of up to 54 patients (TP-0903 monotherapy and combination therapy with ibrutinib).

Additional dose levels, schedules, or disease indications of TP 0903 may be explored, as appropriate, based on the modulation of key biomarkers and the safety profile and clinical signals of activity.

Phase 2 In Phase 2, patients will be enrolled in Group 1 (TP 0903 monotherapy) and Group 2 (TP-0903 combination therapy with ibrutinib) based on the Simon 2 stage design. In Stage 1, up to 13 patients will be enrolled into each patient group (total of 26 patients). If there are no responses among these 13 patients in each group, the study will be stopped. Otherwise, Stage 2 will open to enroll 14 additional patients in each group for a total of 27 patients per group. If 4 or more responses are observed among 27 patients, the conclusion will be that the study treatment is worthy of further investigation.

If both patient groups enroll through Stage 2, it is anticipated that the total enrollment for Phase 2 will be 54 patients.

Arms:
arm 1: Adult patients with CLL/SLL who:

are intolerant to, or have had progressive disease on B-cell receptor antagonists, BCL-2 antagonists or other investigational treatments for CLL/SLL arm 2: Adult patients with CLL/SLL who:

have progression of disease on ibrutinib, yet the treating provider considers continuation of ibrutinib therapy to be in the best interest of the patient

Interventions: intervention 1: TP-0903 intervention 2: TP-0903 and ibrutinib combination therapy
Intervention descriptions: intervention 1: Monotherapy: PHASE 1: TP-0903 will be a 25 mg flat dose. The study drug will be administered orally once daily for 28 days (each cycle is 28 days; no drug-free period).

Patients may continue to receive TP-0903 in 28-day cycles at the same dose given during Cycle 1 until they experience unacceptable toxicity or unequivocal disease progression. No intrapatient escalation of the TP-0903 dose is permitted.

PHASE 2: The starting dose of TP-0903 will be the RP2D determined during Phase 1. TP 0903 will be administered orally at a fixed dose once daily for 28 days (each cycle is 28 days; no drug-free period) with repeated cycles permitted until a patient experiences unacceptable toxicity or unequivocal disease progression. intervention 2: Combination therapy: PHASE 1: TP-0903 and ibrutinib combination therapy: The starting dose of TP-0903 will be a 20 mg flat dose. TP-0903 will be administered orally once daily for 28 days (each cycle is 28 days; no drug-free period). Patients will also receive ibrutinib at the same dose that they were receiving immediately prior to study enrollment.

Patients should continue with the combination of ibrutinib and TP-0903 for at least 3 months after study start.

PHASE 2: The starting dose of TP-0903 will be the RP2D determined during Phase 1. Patients will also receive ibrutinib at the same dose that they were receiving immediately prior to study enrollment. Both TP 0903 and ibrutinib will be administered orally at fixed doses once daily for 28 days (each cycle is 28 days; no drug-free period).

Protocol document:
Prot_000.pdf: 
 
AMENDED CLINICAL STUDY PROTOCOL 
Study Title: 
A Combined Phase 1/2 Study to Investigate the 
Safety, Pharmacokinetics, Pharmacodynamics, and 
Clinical Activity of TP-0903 in Patients with 
Previously Treated Chronic Lymphocytic Leukemia 
(CLL) 
Protocol Number:  
TP-0903-102 Amendment 2 
IND Number: 
139577 
Study Drug/Agents: 
TP-0903
Phase of Development: 
Phase 1/2 
Medical Monitor: 
 
Stephen P Anthony, DO  
VP, Clinical Research 
Tolero Pharmaceuticals, Inc 
Phone: 509-847-5646 
Email: santhony@toleropharma.com
Safety Reporting: 
CRF@couranteoncology.com 
Sponsor Contact: 
 
Susan Smith, RN, MSN 
Senior Director, Drug Development Program & 
Clinical Operations 
Tolero Pharmaceuticals, Inc 
Phone: 210-414-7702 
Email: su.smith@toleropharma.com  
Sponsor: 
Tolero Pharmaceuticals, Inc 
3900 N Traverse Mountain Blvd 
Suite 100 
Lehi, UT USA 84043 
Date of Version Final:  
24 May 2018 
Date of Amendment 1:  
26 June 2018 
Date of Amendment 2:  
13 November 2018 
 
 
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG IS PROVIDED FOR THE 
EXCLUSIVE USE OF INVESTIGATORS OF THIS DRUG AND IS SUBJECT TO RECALL AT ANY TIME. THE 
INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS 
REQUIRED BY FEDERAL OR STATE LAW OR REGULATIONS. SUBJECT TO THE FOREGOING, THIS 
INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS INVOLVED IN THE STUDY WHO HAVE 
A NEED TO KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS INFORMATION. 
THESE RESTRICTIONS ON DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE ORAL OR WRITTEN 
INFORMATION, SUPPLIED TO YOU BY TOLERO PHARMACEUTICALS, INC., WHICH IS DESIGNATED AS 
"PRIVILEGED" OR "CONFIDENTIAL" 


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PROTOCOL SIGNATURE PAGE 
 
SPONSOR SIGNATURE 
I have carefully read the protocol, TP-0903-102 Amendment 2, titled “A Combined Phase 
1/2 Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical 
Activity of TP-0903 in Patients with Previously Treated Chronic Lymphocytic Leukemia 
(CLL)” and confirm that this is the approved current version. 
 
Sponsor’s Signature 
 
Date (DD/MMM/YYYY) 
 
Printed Name 
 
 
INVESTIGATOR’S SIGNATURE 
I have carefully read this protocol, TP-0903-102 Amendment 2, and commit to conduct 
the study as outlined herein, in accordance with the International Council for 
Harmonisation (ICH), Good Clinical Practices (GCPs), and the Declaration of Helsinki, 
and comply with the obligations and requirements of the clinical Investigator and other 
requirements as listed in Title 21 of the United States Code of Federal Regulations (CFR) 
and other applicable regulations. 
 
Investigator’s Signature 
 
Date (DD/MMM/YYYY) 
 
Printed Name 
 
Name of Institution/Research Facility 
 
Phone Number 
 
Email Address 
 
 
Mike Bernstein
Digitally signed by Mike 
Bernstein 
Date: 2018.11.21 11:07:49 -06'00'


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ......................................................................................... 2 
LIST OF TABLES .................................................................................................................... 7 
LIST OF FIGURES .................................................................................................................. 7 
ABBREVIATIONS ................................................................................................................... 8 
PROTOCOL SYNOPSIS ...................................................................................................... 11 
1. 
INTRODUCTION .......................................................................................... 26 
1.1 
Background ...................................................................................................26 
1.2 
Rationale .......................................................................................................27 
2. 
DRUG INFORMATION – TP-0903 .............................................................. 28 
2.1 
Background ...................................................................................................28 
2.2 
Chemistry ......................................................................................................28 
2.3 
Drug Description ............................................................................................29 
2.4 
Mechanism of Action .....................................................................................29 
2.5 
Preclinical Studies .........................................................................................30 
2.5.1 In Vitro Pharmacology ....................................................................................... 30 
2.5.2 In Vivo Pharmacology ....................................................................................... 35 
2.5.3 Safety Pharmacology ........................................................................................ 35 
2.5.4 Nonclinical Absorption, Distribution, Metabolism and Excretion Studies .......... 36 
2.5.5 Animal Toxicology and Pharmacokinetics ........................................................ 39 
2.6 
Clinical Studies ..............................................................................................45 
2.7 
Justification for Study Treatment Plan and Starting Dose ..............................46 
2.8 
Summary of Risk and Benefits .......................................................................46 
3. 
STUDY OBJECTIVES .................................................................................. 48 
4. 
INVESTIGATIONAL PLAN .......................................................................... 50 
4.1 
Overall Study Design .....................................................................................50 
4.2 
Assignment to Treatment ...............................................................................53 
4.3 
Patient Population ..........................................................................................53 
4.3.1 Number of Patients............................................................................................ 53 
4.3.2 Inclusion Criteria................................................................................................ 53 
4.3.3 Exclusion Criteria .............................................................................................. 54 
4.4 
Study Treatment ............................................................................................56 
4.4.1 TP-0903 Administration ..................................................................................... 57 
4.4.2 Ibrutinib Administration ...................................................................................... 57 
4.4.3 Description of Phase 1 and Phase 2 Parts of Study ......................................... 57 
4.4.4 Missed Doses .................................................................................................... 59 


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4.5 
Management of Toxicities and Dosage Modification ......................................59 
4.5.1 Management of Toxicities ................................................................................. 59 
4.5.2 Dose-limiting Toxicities ..................................................................................... 60 
4.5.3 TP-0903 Dose Modifications ............................................................................. 60 
4.5.4 Ibrutinib Dose Modifications .............................................................................. 61 
4.6 
Concomitant Medications and Therapies .......................................................62 
4.6.1 Previous Therapies ........................................................................................... 62 
4.6.2 Concomitant Therapies ..................................................................................... 62 
4.6.3 Birth Control Requirements for Fertile Patients ................................................ 64 
4.7 
Protocol Deviations ........................................................................................64 
5. 
ON-STUDY CLINICAL AND LABORATORY EVALUATIONS ................. 65 
5.1 
Predose Assessments ...................................................................................65 
5.1.1 Screening (Within 14 Days Prior to First Dose) ................................................ 65 
5.1.2 Within 3 Days Prior to First Dose ...................................................................... 66 
5.2 
Treatment Assessments ................................................................................67 
5.2.1 CYCLE 1 ........................................................................................................... 67 
5.2.2 CYCLE 2 ........................................................................................................... 68 
5.2.3 CYCLES 3 ....................................................................................................... 70 
5.3 
End-of-Study Assessments ............................................................................72 
5.4 
30-Day Safety Follow-Up Assessments .........................................................73 
5.5 
Long-term Follow-up for Patient Survival (Phase 2 only) ................................73 
6. 
OFF-STUDY CRITERIA ............................................................................... 74 
6.1 
Withdrawal of Patients ...................................................................................74 
6.2 
Reasons for Withdrawal .................................................................................74 
6.3 
Follow-Up for Patients Withdrawn from Study ................................................74 
6.4 
Termination or Suspension of Study ..............................................................75 
7. 
CRITERIA FOR EVALUATION ................................................................... 76 
7.1 
Safety Endpoints............................................................................................76 
7.2 
Efficacy Endpoints .........................................................................................76 
7.2.1 Response Criteria – 2018 IWCLL Guidelines ................................................... 77 
7.3 
Pharmacokinetic Endpoints ...........................................................................77 
7.4 
Pharmacodynamic Endpoints ........................................................................77 
8. 
ADVERSE EVENTS ..................................................................................... 79 
8.1 
Definitions ......................................................................................................79 
8.2 
Causality ........................................................................................................80 
8.3 
Serious Adverse Events .................................................................................80 
8.4 
Eliciting and Reporting Adverse Events .........................................................80 


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8.5 
Serious Adverse Events and/or Adverse Events Requiring Discontinuation 
of Study Drug .................................................................................................81 
8.6 
Follow-Up of Adverse Events .........................................................................81 
8.7 
Patient Deaths ...............................................................................................82 
8.8 
Reporting Adverse Events to the Regulatory Authorities ................................82 
9. 
STUDY DRUG MANAGEMENT .................................................................. 83 
9.1 
TP-0903 Drug Product ...................................................................................83 
9.2 
Study Drug Dispensing and Accountability.....................................................83 
9.3 
Storage at Study Center ................................................................................83 
9.4 
Compliance ....................................................................................................84 
10. 
RECORD MANAGEMENT ........................................................................... 85 
10.1 Data Collection ..............................................................................................85 
10.2 Source Document Maintenance .....................................................................85 
10.3 Record Maintenance ......................................................................................86 
10.4 Study Center File Management .....................................................................87 
11. 
STATISTICAL ANALYSIS ........................................................................... 88 
11.1 Sample Size ..................................................................................................88 
11.2 Analysis Population Sets ...............................................................................90 
11.3 Data Analyses ...............................................................................................90 
11.3.1 Patient Disposition............................................................................................. 90 
11.3.2 Demographic and Baseline Characteristics ...................................................... 90 
11.3.3 Concomitant Medications .................................................................................. 90 
11.3.4 Treatment Administration/Compliance .............................................................. 91 
11.3.5 Efficacy Analysis ............................................................................................... 91 
11.3.6 Safety Analysis .................................................................................................. 91 
11.3.7 Pharmacokinetic Analysis ................................................................................. 92 
11.3.8 Pharmacodynamic Analysis .............................................................................. 93 
11.4 Interim Analysis .............................................................................................93 
12. 
PROTOCOL AMENDMENTS ...................................................................... 94 
13. 
MONITORING ............................................................................................... 95 
14. 
AUDITING ..................................................................................................... 96 
15. 
ETHICS AND RESPONSIBILITY ................................................................ 97 
15.1 Principal Investigator’s Responsibilities .........................................................97 
15.2 Informed Consent ..........................................................................................97 
15.3 Institutional Review Board .............................................................................98 
16. 
CONFIDENTIALITY ...................................................................................... 99 
17. 
NONPROTOCOL RELATED RESEARCH ............................................... 100 


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18. 
PUBLICATIONS ......................................................................................... 101 
19. 
REFERENCES ............................................................................................ 102 
APPENDIX A – SCHEDULE OF ASSESSMENTS ......................................................... 105 
APPENDIX B – ECOG PERFORMANCE STATUS SCALE ......................................... 108 
APPENDIX C – 2018 IWCLL GUIDELINES GRADING SCALE FOR 
HEMATOLOGIC TOXICITY ........................................................................... 109 
APPENDIX D – NCI COMMON TERMINOLOGY CRITERIA AND GRADING FOR 
ADVERSE EVENTS WHERE THE NCI CTCAE CRITERIA ARE NOT 
APPLICABLE .................................................................................................. 110 
APPENDIX E – LABORATORY TESTS .......................................................................... 111 
APPENDIX F – RESPONSE CRITERIA ........................................................................... 112 
APPENDIX G – CYP2C19 SUBSTRATES, INDUCERS, AND INHIBITORS .............. 113 
APPENDIX H – BASELINE DISEASE ASSESSMENTS ACCORDING TO 2018 
IWCLL GUIDELINES ...................................................................................... 118 
APPENDIX I – PATIENT DOSING DIARY ....................................................................... 119 
 


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LIST OF TABLES 
Table 1. 
Nomenclature and Notable Chemical Characteristics of Both 
Clinical Drug Substance Forms (B and A)................................. 29 
Table 2 
Activity of TP-0903 in Human Cancer Cell Lines ........................... 32 
Table 3 
TP-0903 Proposed Dose Escalation .............................................. 58 
Table 4 
Guide to Dose Adjustments Based on Toxicities ........................... 60 
Table 5 
Sample Size Description ............................................................... 89 
 
LIST OF FIGURES 
Figure 1 
TP-0903 Inhibits GAS6/AXL-mediated Phospho-AKT Activity ....... 31 
Figure 2 
AXL Overexpression and Activation in CLL B-cells Taken  
Directly from Patients .................................................................... 32 
Figure 3 
TP-0903 Potently Induces Apoptosis in CLL Cells Regardless  
of Risk Factors ............................................................................... 33 
Figure 4 
TP-0903 Potently Targets CLL B-cell Viability Even in  
the Presence of BMSCs ................................................................ 33 
Figure 5 
TP-0903 Potently Targets AXL Signaling in CLL B-cell,  
which Correlates with the Induction of Apoptosis  
(Cleaved Caspase3) ...................................................................... 34 
Figure 6 
Induction of Apoptosis by TP-0903 in Lymphocytes from CLL 
Patients Before (Week 0) and After (Weeks 1, 4 and 12) 
Ibrutinib Therapy (3 Samples from Single Patient) ........................ 34 
Figure 7 
Tumor Growth Reduction in Leukemia and Lung Carcinoma 
Mouse Xenograft Models ............................................................... 35 
Figure 8 
Identified Metabolites of TP-0903 Exposed to Human 
Hepatocytes................................................................................... 38 
Figure 9 
Study Design Schema ................................................................... 52 
 


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ABBREVIATIONS 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the plasma concentration curve 
AUC0-12 
Area under the plasma concentration curve from time 0 to 12 hrs 
AUC0-24 
Area under the plasma concentration curve from time 0 to 24 hrs 
AUC0-inf 
Area under the plasma concentration curve from time 0 to infinity 
AUCt 
Area under the plasma concentration curve from time 0 to time t 
AUC0-Tlast 
Area under the plasma concentration curve from time 0 to the time of the 
last concentration 
BP 
Blood pressure 
BMI 
Body mass index 
BMSC 
Bone marrow stromal cells 
BTK 
Bruton’s tyrosine kinase 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CL 
clearance using noncompartmental methods 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
CR 
Complete response (remission) 
CRA 
Clinical research associate 
CRC 
Colorectal cancer 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DLT 
Dose-limiting toxicity 
DoR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
EC50 
Effective concentration in 50% of test subjects 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ELISA 
Enzyme linked immunosorbent assay 
EMT 
Epithelial-to-mesenchymal transition 
FDA 
Food and Drug Administration 
FGFR 
Fibroblast growth factor receptor 
FISH 
Fluorescence in-situ hybridization 
GAS6 
Growth arrest specific 6 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
hERG 
Human ether-a-go-go 


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HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IC50 
Inhibitory concentration in 50% of test subjects 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGHV 
Immunoglobin heavy-chain variable (region) 
IND 
Investigational New Drug (application) 
IO 
Immune-oncology (therapy) 
IRB 
Institutional Review Board 
ITP 
Idiopathic thrombocytopenic purpura 
ITT 
Intent-to-treat 
IWCLL 
International Workshop on CLL 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LN 
Lymph node 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MRT 
Mean residence time 
MTD 
Maximum tolerated dose 
NADPH 
Nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PD 
Pharmacodynamic 
PD 
Progressive disease 
PDAC 
Pancreatic ductal adenocarcinoma 
PET 
Positron emission tomography (scan) 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response (remission) 
PT 
Prothrombin time 
QTcF 
Corrected QT interval (using Fridericia’s correction formula) 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 dose 
RTK 
Receptor tyrosine kinase 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System (software) 
SD 
Stable disease 
SGF 
Simulated gastric fluid 
SLL 
Small Lymphocytic Lymphoma 
SOP 
Standard operating procedure(s) 
t1/2 
Half-life 
t1/2(e) 
Elimination half-life 
TLS 
Tumor lysis syndrome 
Tmax 
Time to maximum observed plasma concentration (peak time) 
TNBC 
Triple negative breast cancer 
TEAE 
Treatment-emergent adverse event 


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ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 


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PROTOCOL SYNOPSIS 
Title of Study: 
A Combined Phase 1/2 Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity of 
TP-0903 in Patients with Previously Treated Chronic Lymphocytic 
Leukemia (CLL) 
Clinical Phase: 
1/2 
Study Indication: 
Previously Treated CLL/SLL (Small Lymphocytic Lymphoma) 
Patient 
Population: 
Adult patients with CLL/SLL who: 
are intolerant to, or have had progressive disease on B-cell receptor 
antagonists, BCL-2 antagonists or other investigational treatments 
for CLL/SLL (Group 1-TP-0903 monotherapy);  
or 
have progression of disease on ibrutinib, yet the treating provider 
considers continuation of ibrutinib therapy to be in the best interest 
of the patient (Group 2-TP-0903 and ibrutinib combination therapy)  
Planned 
Enrollment and 
Study Duration: 
The study is expected to take up to 36 months to enroll up to 
108 patients (up to 27 patients in each group (Group 1 and Group 2) 
in both Phase 1 (n=54) and Phase 2 (n=54). 
Objectives: 
Phase 1  
Primary: 
x 
To characterize the safety and toxicity profile of TP-0903 when 
administered orally once daily for 28 days (each cycle is 
28 days; no drug-free period) in the following patient groups: 
o Group 1 (TP-0903 monotherapy): those with CLL/SLL 
who are intolerant to, or have had progressive disease 
on B-cell receptor antagonists, BCL-2 antagonists or 
other investigational treatments for CLL/SLL   
o Group 2 (TP-0903 and ibrutinib combination therapy): 
those with CLL/SLL who have progressed on ibrutinib, 
yet the treating provider considers continuation of 
ibrutinib therapy to be in the best interest of the patient.   
x 
To determine the Recommended Phase 2 Dose (RP2D) of 
TP-0903 when administered orally on this schedule to the 
defined patient groups 
Secondary: 
x 
To observe patients for any evidence of antileukemic activity of 
oral TP-0903 by determining the Objective Response Rate 
([ORR], ie, rate of complete response [CR] plus rate of partial 
response [PR] in the defined patient groups according to 
guidelines set forth by the 2018 International Workshop on CLL 
(IWCLL)  
x 
To evaluate the pharmacokinetics (PK) of oral TP-0903 in the 
defined patient groups 


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Exploratory: 
x 
To study potential biomarkers relevant to disease and  
pharmacodynamics (PD) of oral TP-0903 in the defined patient 
groups through assessment of analytes including, but not 
limited to, soluble AXL, AXL expression and phosphorylation, 
growth 
arrest 
specific 
6 
(GAS6), 
and 
mesenchymal 
transcription factors in peripheral blood samples and bone 
marrow 
Phase 2 
Primary: 
x 
To determine the ORR in the two defined patient groups 
according to guidelines set forth by the 2018 IWCLL 
Secondary: 
x 
To determine the Duration of Response (DoR, ie, the time from 
tumor response to disease progression) 
x 
To determine the Progression-free Survival (PFS, ie, the time 
from first dose to objective tumor progression or death) 
x 
To determine the rate of Overall Survival (OS, ie, the time from 
first dose to death from any cause) 
Exploratory: 
x 
To study potential biomarkers relevant to disease and  
pharmacodynamics (PD) of oral TP-0903 in the defined patient 
groups through assessment of analytes including, but not 
limited to, soluble AXL, AXL expression and phosphorylation, 
growth 
arrest 
specific 
6 
(GAS6), 
and 
mesenchymal 
transcription factors in peripheral blood samples and bone 
marrow 
Study Design: 
This is a combined Phase 1/2 study of oral TP-0903 in patients with 
previously treated CLL/SLL. In both Phase 1 and Phase 2, study 
participants will be assigned to one of two defined patient groups: 
x 
Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who 
are intolerant to, or have progressed on, B-cell receptor 
antagonists and/or BCL-2 antagonists  
x 
Group 2 (TP-0903 and ibrutinib combination therapy): Patients 
with CLL/SLL who have progressed on ibrutinib, yet the treating 
provider considers continuation of ibrutinib therapy to be in the 
best interest of the patient.  
Both groups of patients will be treated identically with TP-0903 and 
will undergo the same study assessments. 
Phase 1 
Patients will be enrolled in Group 1 and Group 2 in cohorts of 3 to 
6 patients simultaneously. Group 2 will start at one dose level below 
the Group 1 starting dose. In each group, escalation of the TP-0903 
dose will follow a standard 3+3 design with sequential cohorts of 


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TOLERO PHARMACEUTICALS, INC 
three patients treated with incrementally higher doses of TP-0903 
until a dose-limiting toxicity (DLT) is observed and the maximum 
tolerated dose (MTD) is established. Once the first patient at a dose 
level is enrolled, the second and third patients may be enrolled after 
3 weeks if the initial patient has not experienced a DLT or any 
unacceptable toxicity. 
If 1 of 3 patients in a cohort experiences a DLT, up to 3 additional 
patients will be treated at that dose level. If no additional DLTs are 
observed in the expanded 3- to 6-patient cohort within 28 days after 
the last patient was first dosed, the dose will be escalated in a new 
cohort of 3 patients. If 2 or more of 3 to 6 patients at a given dose 
level experience a DLT during the first cycle, then the MTD will have 
been exceeded and up to a total of 6 patients will be treated at the 
previous lower dose level. If 0 or 1 of 6 patients experiences a DLT 
at this previous lower dose level, this dose will be declared the 
MTD. 
7KH 07' LV GHILQHG DV WKH GRVH DW ZKLFK  RI  SDWLHQWV
experience a DLT during Cycle 1 with the next higher dose having 
at least 2 of 3 to 6 patients experiencing a DLT during Cycle 1. 
Once the MTD or preliminary RP2D is identified, an expansion 
cohort of up to 6 patients will be enrolled in each patient group to 
confirm safety/suitability of the preliminary RP2D, to collect 
additional biomarker data, and to further explore efficacy. 
It is expected that up to 27 patients will be enrolled in each patient 
group for a total of up to 54 patients (TP-0903 monotherapy and 
combination therapy with ibrutinib). 
Additional dose levels, schedules, or disease indications of 
TP-0903 may be explored, as appropriate, based on the modulation 
of key biomarkers and the safety profile and clinical signals of 
activity. 
Phase 2 
In Phase 2, patients will be enrolled in Group 1 (TP-0903 
monotherapy) and Group 2 (TP-0903 combination therapy with 
ibrutinib) based on the Simon 2-stage design. In Stage 1, up to 
13 patients will be enrolled into each patient group (total of 
26 patients). If there are no responses among these 13 patients in 
each group, the study will be stopped. Otherwise, Stage 2 will open 
to enroll 14 additional patients in each group for a total of 
27 patients per group. If 4 or more responses are observed among 
27 patients, the conclusion will be that the study treatment is worthy 
of further investigation. When the true response rate of 20% 
(alternative hypothesis) is tested against the null hypothesis 
response rate of 5%, this design yields a Type I error rate of 0.05 
and power of 80%.  
If both patient groups enroll through Stage 2, it is anticipated that 
the total enrollment for Phase 2 will be 54 patients. 


Protocol No. TP-0903-102 Amendment 2 
 
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Any patient who withdraws from the study for treatment-related 
toxicity prior to being evaluated for response in Phase 2 will be 
considered a nonresponder. Patients who drop out of the study for 
other reasons prior to being assessed for response will be 
considered unevaluable and may be replaced. Enrollment in either 
patient group may be stopped at any poiQWRQFHSDWLHQWVKDYH
had a response to treatment, but the maximum enrollment in each 
patient group in Phase 2 will be 27 evaluable patients. 
Supportive Care Measures 
Supportive care will include: 
x 
Careful monitoring of patients at high risk for tumor lysis 
syndrome (TLS) LHSDWLHQWVZLWKDQ\O\PSKQRGH>/1@FP
RU DEVROXWH O\PSKRF\WH FRXQW >$/&@  î9/L and any LN 
 cm) by collection of blood and real-time (STAT) review of 
TLS laboratory parameters (ie, uric acid, potassium, phosphate, 
calcium, and creatinine) on Day 1 of Cycle 1 at baseline 
(predose) and at 6 hours and 24 hours post dose. 
x 
Infection Prevention (ie, prophylactic antibiotic, antiviral, and/or 
antifungal therapy) to be initiated according to each institution’s 
standardized protocols 
Inclusion 
Criteria: 
To be eligible for participation, patients must meet all of the 
following inclusion criteria: 
1. 
Are \HDUV old 
2. 
Have an established, pathologically confirmed diagnoses of 
CLL/small lymphocytic lymphoma (SLL) requiring therapy 
according to the 2018 IWCLL guidelines  
3. 
Have received at least one prior therapy for CLL/SLL and can 
be classified in one of two patient groups: 
x 
Group 1 (TP-0903 monotherapy): Patients with CLL/SLL 
who are intolerant to, or have had progressive disease 
on B-cell receptor antagonists, BCL-2 antagonists or 
other investigational treatments for CLL/SLL   
x 
Group 2 (TP-0903 and ibrutinib combination therapy): 
Patients with CLL/SLL who have progressed on ibrutinib, 
yet the treating provider considers continuation of 
ibrutinib therapy to be in the best interest of the patient. 
4. 
Have an Eastern Cooperative Oncology Group (ECOG) 
performance staWXV 
5. 
Have adequate hematologic function: 
x 
$EVROXWHQHXWURSKLOFRXQW$1&500/μL 
x 
3ODWHOHWFRXQW30,000/μL 
x 
+HPRJORELQJG/ in the absence of transfusions within 
the previous 2 weeks  
 
 


Protocol No. TP-0903-102 Amendment 2 
 
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6. 
Have adequate organ function: 
x 
&UHDWLQLQHFOHDUDQFHP/PLQ 
x 
Alanine 
aminotransferase 
(ALT)/ 
aspartate 
aminotransferase (AST) level 2.5 îupper limit of normal 
(ULN) 
x 
+DYHDWRWDOELOLUXELQOHYHOî8/1XQOHVVVHFRQGDU\
to Gilbert syndrome, hemolysis, or leukemia) 
7. 
Have acceptable coagulation status: 
x 
Activated partial thromboplastin (aPTT) and prothrombin 
WLPH375 î8/1 
8. 
Have a negative pregnancy test (in females of childbearing 
potential) 
9. 
Be nonfertile or agree to use an adequate method of 
contraception. Sexually active patients and their partners must 
use an effective method of contraception (hormonal or barrier 
method of birth control, or abstinence) prior to study entry and 
for the duration of study participation and for at least  30 days 
after the last study drug dose. Should a woman become 
pregnant or suspect that she is pregnant while participating in 
this study, she should inform her treating physician 
immediately 
10. Have read and signed the Institutional Review Board 
(IRB)-approved informed consent form (ICF) prior to any 
study-related procedure. (In the event that the patient is 
rescreened for study participation or a protocol amendment 
alters the care of an ongoing patient, a new ICF must be 
signed.) 
11. Are able to comply with the requirements of the entire study 
Exclusion 
Criteria: 
Patients meeting any one of these exclusion criteria will be 
prohibited from participating in the study. 
1. 
Have undergone prior autologous or allogeneic stem cell 
WUDQVSODQW ZLWKLQ  PRQWKV KDYH QRW UHFRYHUHG IURP
transplant associated toxicities, or requires graft versus host 
immunosuppressive therapy 
2. 
Have known central nervous system (CNS) involvement 
3. 
Have Richter’s transformation of CLL  
4. 
Have received any monoclonal antibody therapy directed at 
treatment of the patient’s malignancy within 2 weeks prior to 
anticipated first dose 
5. 
Have 
received 
any 
anticancer 
therapy 
including 
chemotherapy, radiotherapy, or an investigational anticancer 
drug within less than 5 half-lives of the last dose of that 
treatment 


Protocol No. TP-0903-102 Amendment 2 
 
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x 
This exclusion criterion is not applicable to patients 
requiring continuation on ibrutinib. (Note: Certain patients 
with a rapidly rising white blood cell count while on ibrutinib 
may need to remain on this drug for medical reasons. 
These patients will need to be approved by the Medical 
Monitor and treated in accordance with the protocol.) 
6. 
Have received >20 mg/day of prednisone and 0.1 mg/day of 
mineralocorticoids within 7 days prior to anticipated first dose 
7. 
Have a corrected QT interval of >450 msec (males) and 
>470 msec (females) using Fridericia’s correction formula 
8. 
Have a significant history of renal, neurologic, psychiatric, 
endocrinologic, 
metabolic, 
immunologic, 
hepatic, 
or 
cardiovascular disease or any other medical condition that, in 
the opinion of the Investigator, would adversely affect his/her 
participation in the study 
9. 
Are pregnant and/or nursing, or refuse to use appropriate 
contraceptives during the course of the study and for at least 
30 days after the last dose of study drug 
10. History of another malignancy in the last 5 years except for the 
following adequately treated: 
x 
Local basal cell or squamous cell carcinoma of the skin 
x 
Carcinoma in situ of the cervix or breast 
x 
Papillary, noninvasive bladder cancer 
x 
Early stage prostate cancer for which observation is 
clinically indicated  
x 
Other Stage 1 or 2 cancers currently in complete 
remission 
x 
Any other cancer that has been in complete remission for 
2 years or surgically cured. The Medical Monitor may be 
contacted for additional determination of acceptable prior 
cancer history.   
11. Have known gastrointestinal disorders (eg, malabsorption 
syndrome), complications (eg, dysphagia), or surgery that 
could make consumption or absorption of oral medications 
problematic 
12. Have an uncontrolled systemic infection (viral, bacterial, or 
fungal) or fever and neutropenia within 7 days prior to 
anticipated first dose 
13. Have active and uncontrolled autoimmune cytopenias for 2 or 
more weeks including autoimmune hemolytic anemia (AIHA) or 
idiopathic thrombocytopenic purpura (ITP)  
14. Have received prior therapy with an AXL inhibitor 


Protocol No. TP-0903-102 Amendment 2 
 
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15. Have exhibited allergic reactions to a similar structural 
compound, biological agent, or formulation 
16. Are unwilling or unable to comply with procedures required in 
this protocol 
17. Have a history of severe adverse reaction (eg, hypersensitivity 
reaction, anaphylaxis) to sulfonamides 
Study 
Treatment: 
Phase 1 
x 
The starting dose for TP-0903 in Group 1 (monotherapy) will be 
a 25-mg flat dose. The study drug will be administered orally 
once daily for 28 days (each cycle is 28 days; no drug-free 
period). 
Patients may continue to receive TP-0903 in 28-day cycles at 
the same dose given during Cycle 1 until they experience 
unacceptable toxicity or unequivocal disease progression. No 
intrapatient escalation of the TP-0903 dose is permitted.  
x 
Group 2 (TP-0903 and ibrutinib combination therapy): The 
starting dose of TP-0903 will be a 20-mg flat dose. TP-0903 will 
be administered orally once daily for 28 days (each cycle is 
28 days; no drug-free period). Patients will also receive ibrutinib 
at the same dose that they were receiving immediately prior to 
study enrollment.  
Patients should continue with the combination of ibrutinib and 
TP-0903 for at least 3 months after study start. After that time, 
patients can either continue with combination therapy or 
discontinue ibrutinib and continue with TP-0903 monotherapy 
at the discretion of the Investigator in consultation with the 
Medical Monitor. Patients may continue to receive TP-0903 in 
28-day cycles at the same dose given during Cycle 1 until they 
experience unacceptable toxicity or unequivocal disease 
progression. Ibrutinib may be stopped and reinitiated at the 
discretion of the Investigator and in consultation with the 
Medical Monitor; however, the total time patients may receive 
treatment with ibrutinib is 2 years.  
Phase 2 
x 
Group 1 (TP-0903 monotherapy): The starting dose of TP-0903 
will be the RP2D determined during Phase 1. TP-0903 will be 
administered orally at a fixed dose once daily for 28 days (each 
cycle is 28 days; no drug-free period) with repeated cycles 
permitted until a patient experiences unacceptable toxicity or 
unequivocal disease progression. 
x 
Group 2 (TP-0903 and ibrutinib combination therapy): The 
starting dose of TP-0903 will be the RP2D determined during 
Phase 1. Patients will also receive ibrutinib at the same dose 
that they were receiving immediately prior to study enrollment. 
Both TP-0903 and ibrutinib will be administered orally at fixed 


Protocol No. TP-0903-102 Amendment 2 
 
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13 November 2018 
 
 
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TOLERO PHARMACEUTICALS, INC 
doses once daily for 28 days (each cycle is 28 days; no drug-
free period).  
Patients should continue with the combination of ibrutinib and 
TP-0903 for at least 3 months after study start. After that time,  
patients can either continue with combination therapy or 
discontinue ibrutinib and continue with TP-0903 monotherapy at 
the discretion of the Investigator in consultation with the Medical 
Monitor. Patients may continue to receive TP-0903 in 28-day 
cycles at the same dose given during Cycle 1 until they 
experience unacceptable toxicity or unequivocal disease 
progression. Ibrutinib may be stopped and reinitiated at the 
discretion of the Investigator in consultation with the Medical 
Monitor; however, the total time patients may receive treatment 
with ibrutinib is 2 years.  
Study 
Assessments: 
These assessments will be conducted during both the Phase 1 and 
Phase 2 studies. 
Predose 
Screening/Baseline Period (Within 14 Days Prior to First Dose): 
x 
Complete medical history including histologically confirmed 
diagnosis of CLL/SLL 
x 
Conduct full physical examination, including height (cm), weight 
(kg), and review the following constitutional symptoms 
suggestive of active disease: 
o 8QLQWHQWLRQDOZHLJKWORVVZLWKLQSUHYLRXV months 
o Marked fatigue 
o )HYHUV)RU&IRUZHHNVZLWKRXWHYLGHQFH
of infection 
o 1LJKWVZHDWVIRUPRQWKZLWKRXWHYLGHQFHRILQIHFWLRQ 
x 
Record vital signs (body temperature, respirations, heart rate, 
and blood pressure) 
x 
Assess ECOG Performance Status (Appendix B) 
x 
Assess baseline disease status according to 2018 IWCLL 
guidelines (Appendix H) within 28 days of Cycle 1 Day 1: 
o Perform a computed tomography (CT) scan of neck, chest, 
abdomen, and pelvis for evaluation of lymphadenopathy, 
hepatomegaly, and splenomegaly; (within 28 days of 
Cycle 1 Day 1) 
o Collect bone marrow and aspirate with matched peripheral 
blood sample 
o The following should be obtained (within 28 days of Cycle 1 
Day 1): 
 
Molecular cytogenetics FISH (Fluorescence in Situ 
Hybridization) for del(13q), del(11q), del(17p), add(12) 
[peripheral blood] 
 
Karyotyping with CpG (or institutional standard) 
stimulation [bone marrow] 


Protocol No. TP-0903-102 Amendment 2 
 
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IND No. 139577 
 
 
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 
TP53 mutation analysis [peripheral blood] 
 
IGHV (Immunoglobulin Heavy-chain Variable region) 
mutational analysis [peripheral blood] 
x 
PET (Positron Emission Tomography) scan to assess for 
possible Richter’s transformation (within 14 days of first dose) 
x 
Evaluate laboratory parameters (Appendix E): 
o Hematology (complete blood count [CBC] with differential 
and platelet count) 
o Full serum chemistry panel 
o Coagulation parameters (PT and aPTT) 
o Urinalysis 
o Serum immunoglobulins 
o Direct antiglobulin 
o Serum ß2-microglobulin 
x 
Perform 
12-lead 
electrocardiogram 
(ECG) 
including 
assessment of QTcF 
x 
Serum or urine pregnancy test in females of childbearing 
potential 
x 
Record concomitant medications (including all prescription 
drugs, nonprescription drugs, and nutritional supplements 
within the past 14 days 
 
Within 72 hours of C1D1: 
(not required to be repeated at Cycle 1 Day 1 if within 3 days prior 
to first dose) 
x 
Conduct full physical examination, including weight (kg) 
x 
Record vital signs (body temperature, respirations, heart rate, 
and blood pressure) 
x 
Evaluate laboratory parameters (hematology and full serum 
chemistry panel) 
x 
Record concomitant medications 
x 
Serum or urine pregnancy test in females of childbearing 
potential 
x 
Review all inclusion/exclusion criteria to determine patient 
eligibility  
 
Treatment Period 
x 
Day 1 of each cycle 
o Full physical examination, including weight (kg) 
o Record vital signs prior to first dose 
o Assess ECOG Performance Status 
o Assess TLS labs (Cycle 1/Day 1 only) 
o Serum or urine pregnancy test in females of childbearing 
potential 


Protocol No. TP-0903-102 Amendment 2 
 
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13 November 2018 
 
 
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TOLERO PHARMACEUTICALS, INC 
 
 
 
o Perform 12-lead ECG including assessment of QTcF 
x 
Weekly (Days 1, 8, 15, 22) unless otherwise noted 
o Abbreviated physical examination (adverse event [AE]- or 
symptom directed) (exclude Day 1) 
o Vital signs (body temperature, respirations, heart rate,  
blood pressure) 
o Evaluate laboratory parameters (hematology and full serum 
chemistry panel) 
o Record concomitant medications 
o Assess for AEs 
x 
Day 28 of Cycle 2 and every EVEN cycle thereafter (ie, Cycle 4, 
Cycle 6, etc) 
o Response assessments per 2018 IWCLL guidelines 
(Appendix F) 
o CT scan of neck, chest, abdomen, and pelvis for evaluation 
of lymphadenopathy, hepatomegaly, and splenomegaly 
o Review of the following constitutional symptoms suggestive 
of active disease: 
 
8QLQWHQWLRQDO ZHLJKW ORVV  ZLWKLQ SUHYLRXV
6 months 
 
Marked fatigue (ie, ECOG PS 2 or worse) 
 
)HYHUV ) RU & IRU  ZHHNV ZLWKRXW
evidence of infection 
 
1LJKWVZHDWVIRUPRQWKZLWKRXWHYLGHQFHRILQIHFWLRQ 
x 
If clinical and laboratory results indicate possible CR:  
o Collect bone marrow and aspirate with matched peripheral 
blood sample for CBC and determination of MRD (central 
lab assessment) 
 
Long-term Follow-up for Patient Survival (Phase 2 only) 
All patients enrolled and treated in the Phase 2 study will be 
contacted by telephone to assess for date of death, date of relapse, 
or continued remission beginning the month after the patient 
completes the end-of-study assessments up to a maximum of 
2 years regardless of how many treatment cycles a patient 
receives. 
Year 
Phone Calls 
1 
(Date of 30-Day FU + 12 mths) 
Every month 
2 
(14 - 24 mths after Date of 30-Day FU) 
Every other month 
 


Protocol No. TP-0903-102 Amendment 2 
 
Final 
IND No. 139577 
 
 
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Pharmacokinetic 
Assessments: 
Plasma PK analysis of oral TP-0903 will be performed at protocol-
specified time points during Cycle 1 in all patients enrolled in the 
Phase 1 study (Section 7.3). Known metabolites of TP-0903, if any, 
may also be evaluated. No PK assessments will be conducted 
during Phase 2. 
Standard plasma PK parameters will be calculated, including: 
maximum observed plasma concentration (Cmax), time to Cmax (peak 
time) (Tmax), area under the plasma concentration curve (AUC) from 
time 0 to 24 hours (AUC0-24), AUC from time 0 to infinity (AUC0-inf), 
AUC from time 0 to time t (AUCt), half-life (t1/2), and clearance using 
noncompartmental methods (CL). 
If data permit, dose proportionality and accumulation ratio will be 
estimated in Phase 1 Cycle 1. 
Pharmacodynamic 
Assessments: 
Potential biomarker assessments will be evaluated during Phase 1 
and Phase 2 (Section 7.4) as follows: 
x 
Blood for potential biomarker assessments including, but not 
limited to, soluble AXL, AXL expression and phosphorylation, 
GAS6 and mesenchymal transcription factors   
Safety Endpoints: 
Safety will be monitored from the time of the first dose until 30 days 
after the last dose of TP-0903. During Phase 1, the safety endpoints 
will be evaluated after Cycle 1. The dose escalation committee will 
have access to complete safety profiles of all patients receiving 
TP-0903 to enable decision making. 
The primary safety endpoint is to assess the tolerance and toxicity 
of continuous orally administered TP-0903 through evaluation of 
physical examinations, vital signs, laboratory parameters, solicited 
and unsolicited adverse events (AEs) including DLTs, and all 
causes of mortality up to 30 days from the last dose in both phases 
of the study.  
Overall safety profile will be characterized by type, frequency, 
severity, seriousness, timing, duration, and relationship of study 
drug to AEs and laboratory abnormalities. 
Treatment-emergent adverse events (TEAEs), namely, those with 
initial onset or that worsen in severity after the first dose of TP-0903 
will be classified using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.0 or higher and graded according 
to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. 
All DLTs will be reported and the MTD and RP2D identified. 
A Data Safety Monitoring Board (DSMB) will monitor key outcomes 
from the study during the Phase 2 study. 


Protocol No. TP-0903-102 Amendment 2 
 
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IND No. 139577 
 
 
13 November 2018 
 
 
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TOLERO PHARMACEUTICALS, INC 
DLT Definitions: 
Phase 1 
A DLT is defined as any one of the following events observed 
within Cycle 1, regardless of attribution unless clearly and 
incontrovertibly related to the underlying disease or extraneous 
causes (such as progressive disease; other decreases in the 
white blood cell count, or in circulating granulocytes, are not 
to be considered, since a decrease in the white blood cell 
count is a desired therapeutic endpoint): 
x 
Any Grade  nonhematologic toxicity 
x 
Any Grade 3 AE WKDW GRHV QRW UHVROYH WR *UDGH 1 within 
72 hours with use of supportive care 
x 
$Q\$67DQG$/7HOHYDWLRQîULN accompanied by serum 
bilirubin levels >2 îULN 
x 
Any Grade  HOHFWURO\WH GLVWXUEDQFHV HJ K\SHUNDOHPLD
hypophosphatemia, hyperuricemia) that do not resolve within 
<72 hours 
x 
$Q\*UDGHHOHYDWLRQVLQFUHDWLQLQH 
x 
Any Grade 5 toxicity 
x 
Any instance of febrile neutropenia 
Efficacy Endpoints: 
Phase 2 
The primary efficacy endpoint of the Phase 2 study is to determine 
the ORR (rate of CRs plus PRs) in the defined patient groups 
according to guidelines set forth by the 2018 IWCLL. 
Secondary efficacy endpoints include: 
x 
DoR 
x 
PFS 
x 
OS 
Efficacy assessments will be performed on Day 28 of Cycle 2 and 
then every even cycle thereafter (ie, Cycle 4/Day 28, Cycle 6/Day 
28, etc). Response rates will be calculated in Stage 1 and Stage 2 
as per the Simon 2-stage design. 
Pharmacokinetic 
Endpoints: 
Blood samples will be collected from all patients enrolled in the 
Phase 1 study for plasma PK analysis of oral TP-0903 (Section 7.3) 
at the following time points: 
Cycle 
Day 
Time Points 
1 
1 
Predose, 1 hr, 2 hrs, 6 hrs 
2 
Predose / 24 hr post Day 1 dose 
28 
Predose, 1 hr, 2 hrs, 6 hrs 
2 
1 
Predose / 24 hr post Day 28 dose 
  3+ 
1 
Predose 
 


Protocol No. TP-0903-102 Amendment 2 
 
Final 
IND No. 139577 
 
 
13 November 2018 
 
 
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TOLERO PHARMACEUTICALS, INC 
Pharmacodynamic 
Endpoints: 
Blood samples will be collected from all patients during each cycle 
in the Phase 1 and Phase 2 studies for analysis of potential 
biomarkers. (Section 7.4) at the following time points: 
Cycle 
Day 
Time Points 
1 
1 
Predose, 2 hrs, 6 hrs 
2 
Predose / 24 hr post Day 1 dose 
8 
Predose 
2+ 
1 
Predose  
End of Study 
-- 
-- 
 
Statistical Analysis: Sample Size 
Phase 1 
Based on the standard oncology 3+3 dose escalation design, the 
total number of patients to be enrolled cannot be precisely 
determined as the sample size is dependent upon the observed 
safety profile, which will determine the number of patients per dose 
cohort, as well as the number of dose escalations required to 
achieve the MTD. It is anticipated that 12 to 21 patients will be 
required to achieve MTD dose level. Once the MTD or preliminary 
RP2D is identified, an expansion cohort of approximately six 
patients will be enrolled in each patient group to confirm 
safety/confirm the suitability of the preliminary RP2D, to collect 
additional biomarker data, and to further explore efficacy. It is 
expected that up to 27 patients will be enrolled in each patient group 
(Group 1: TP-0903 monotherapy and Group 2: TP-0903 
combination therapy with ibrutinib). 
Phase 2 
The statistical power calculations for each patient group 
(monotherapy and combination therapy) are based on the Simon 
2-stage minimax design. In Stage 1, up to 13 evaluable patients will 
be enrolled and treated at the RP2D identified in the Phase 1 part 
of this study. Stage 2 may be initiated at any point after confirming 
a response (CR or PR) in at least one Stage 1 patient. If there are 
no responders among 13 evaluable Stage 1 patients, the study will 
be stopped after Stage 1. In Stage 2, 14 patients will be enrolled to 
bring the total enrollment in Phase 2 (including Stage 1 patients) to 
27 evaluable patients. Stage 2 patients will also receive the RP2D 
dose identified in the Phase 1 study. If 4 or more responses are 
observed in 27 patients, the conclusion will be that the combination 
regimen is worthy of further investigation. When the true response 
rate of 20% (alternative hypothesis) is tested against the null 
hypothesis response rate of 5%; this design yields a Type I error 
rate of 0.05 and power of 80%. If both patient groups (TP-0903 
monotherapy and combination therapy with ibrutinib) enroll through 
Stage 2, it is anticipated that the total enrollment for Phase 2 will be 
54 patients (Group 1: TP-0903 monotherapy [n=27] and Group 2: 
combination therapy [n=27]). 
 
 


Protocol No. TP-0903-102 Amendment 2 
 
Final 
IND No. 139577 
 
 
13 November 2018 
 
 
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TOLERO PHARMACEUTICALS, INC 
Safety Analysis 
All patients who receive any dose of TP-0903 will be included in the 
summaries and listings of safety data. 
In all summaries, emphasis will be placed on TEAEs. AEs will be 
summarized by the frequency of patients experiencing TEAEs 
corresponding to body systems and MedDRA preferred term and 
by worst NCI CTCAE v5.0 grade. Summaries will also be provided 
of TEAEs judged by the investigator to be related or possibly related 
to TP-0903 and/or combination therapy. 
AEs resulting in discontinuation of TP-0903 treatment or withdrawal 
from the study, Grade 3 or higher, serious adverse events (SAEs), 
and deaths on-study will be tabulated. All DLTs will be reported and 
the MTD and RP2D identified. 
Other safety assessments (eg, clinical laboratory parameters, vital 
signs, and ECG) will be summarized for each TP-0903 dose level 
by observed values at each assessment and changes from 
baseline using descriptive statistics. 
 
Efficacy Analysis 
ORR will be summarized by number and percentage of patients 
meeting the definition of ORR along with the corresponding exact 
95% confidence intervals. 
Time-to event endpoints (DoR, PFS, and OS) will be summarized 
by Kaplan-Meier methods (median, 95% confidence interval (CI), 
number of events, number censored, and Kaplan-Meier figures). 
Additional analyses may be performed to assist the Sponsor in 
planning future studies. 
 
Pharmacokinetic Analysis 
PK parameters will be estimated using standard noncompartmental 
analysis and according to FDA guidance. Actual sample collection 
times will be used rather than scheduled collection times.  
Plasma concentrations of oral TP-0903 will be summarized by 
descriptive statistics, including mean, n, standard deviation, 
coefficient of variation, minimum, maximum, and median. A 
validated bioanalytical method for the detection of TP-0903 in 
human plasma has been developed prior to this study to establish 
assay sensitivity, specificity, linearity, and reproducibility. 
Plasma concentrations below the limit of quantification will be 
treated as “0”. Imbedded missing plasma concentrations (ie, 
missing values between 2 observed values) will be estimated using 
linear extrapolation. This is consistent with using the trapezoidal 
rule to calculate AUC. Other missing plasma concentrations will be 
excluded from calculations to estimate PK parameters. 
If data permit, dose proportionality and accumulation ratio will be 
estimated in Phase 1 Cycle 1. 


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Pharmacodynamic Analysis  
The PD relationships of TP-0903 exposure with exploratory 
biomarkers will be quantified using the Spearman rank correlation 
statistic to examine the relationships between response and 
treatment (ordered categorical dependent variables) and changes 
from baseline values of PD endpoints (continuous independent 
variables). 
 
Interim Analysis 
In Phase 1, safety data will be monitored continuously per standard 
Phase 1 oncology study practices. 
In Phase 2, since the Simon 2-stage design will be employed, 
response rate data will be assessed after Stage 1 and Stage 2. 


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1. 
INTRODUCTION 
1.1 Background 
TP-0903 is an inhibitor of AXL kinase, which is known to be a central regulator of 
oncogenesis and a driver of resistant cancer phenotypes [1]. AXL is a receptor tyrosine 
kinase (RTK) that is upregulated in many hematological malignancies and solid tumors 
[2]. It is involved in multiple cancer-promoting biological processes including cell 
proliferation, differentiation, motility, and survival. Along with its other family members, 
MER and TYRO3, AXL is an important regulator of the mesenchymal phenotype which 
allows cancer cells to grow in an anchorage-independent manner, metastasize, and 
most importantly, drive resistance to targeted cancer therapeutics, traditional 
chemotherapies, and immuno-oncology agents [3, 4, 5]. 
TP-0903 has shown potent inhibition of AXL kinase and other TAM family members in 
a biochemical kinase assay. TP-0903 demonstrates corresponding activity in cancer 
cell lines and mouse xenograft efficacy models. TP-0903 is shown to block cancer cell 
epithelial-to-mesenchymal transitions, as evidenced by decreased cancer cell 
migration induced by the AXL receptor ligand, growth arrest specific 6 (GAS6), and 
decreased expression of mesenchymal cell markers, such as Slug and Snail. TP-0903 
is shown to inhibit the phosphorylation of AKT as a result of GAS6 treatment in multiple 
cancer cell lines. TP-0903 is shown to be antiproliferative towards cancer cell lines in 
culture with effective concentration (EC50) values in the submicromolar range. 
Treatment with TP-0903 is shown to cause tumor regressions (>100% tumor growth 
inhibition) in mouse xenograft efficacy models of acute myeloid leukemia (AML), 
non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), 
colorectal carcinoma (CRC), ovarian cancer, and other tumor models using 
well-tolerated dosing regimens. Additionally, TP-0903 has potent activity at modulating 
the immune system and demonstrates activity in an immune-competent syngenic 
model of triple negative breast cancer (TNBC) both as a single agent and in 
combination with immune-oncology (IO) therapies. 
Several hematological malignancies are dependent on aberrant AXL signaling for 
sustained survival through pro-survival and cross-talk to other RTK pathways, such as 
fibroblast growth factor receptor (FGFR) [6, 7]. Therefore, targeting hematological 
malignancies with TP-0903 as a single agent to down-regulate AXL-dependent 
signaling pathways is a strategy of high interest. AXL was identified as a potential 
therapeutic target in chronic lymphocytic leukemia (CLL) by studying the interaction 
between CLL B-cells and bone marrow stromal cells (BMSC). It was found that CLL 
utilizes microvesicles to constitutively activate AXL signaling in both the diseased 
B-cells and the associated BMSCs [8]. TP-0903 was shown to induce apoptosis in 
CLL B-cells taken directly from patients at concentrations as low as 100 nM [6]. 
Importantly, this was observed when the CLL B-cells were cocultured in the protected 
niche of BMSCs. TP-0903 was equally potent against CLL cells regardless of risk 
factor. Indeed, CLL patients with 17p/TP53-deletions have an upregulated AXL 
dependency [9]. Current treatment is different for 17p/P53-deletion patients given the 
aggressive nature of this disease and the lack of curable therapy for this subtype. In 
addition, those patients with CLL who have been previously treated with ibrutinib 
become resistant to ibrutinib and, therefore, would benefit from this treatment as it 
appears that AXL inhibition works in circumstances where Bruton's tyrosine kinase 
(BTK) inhibitors have lost their efficacy [6]. Note, ibrutinib as a single agent has not 


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been demonstrated to be curative in relapsed/refractory CLL. Biomarkers to help 
define which CLL patients derive the maximal benefit seem to be very unclear at this 
time. Some previously published studies have suggested that 20% expression of AXL 
in CLL patients would be a good target patient population for drugs such as TP-0903. 
However, no absolute threshold of AXL expression seems to correlate to TP-0903 
response [6]. Clearly, there is an unmet medical need for patients with CLL who have 
17p/TP53-deletions and those patients who have progressed following treatment with 
a BTK inhibitor. 
In preclinical studies, it is shown that TP-0903 is not a significant inhibitor of in vitro 
human ether-à-go-go-related gene (hERG) channel activity at submicromolar 
concentrations [10, 11]. Good Laboratory Practice (GLP) toxicology studies in rats and 
dogs have shown that TP-0903 is generally well tolerated at the doses that were 
evaluated [12, 13]. Potential target organs of toxicity include the bone marrow, 
gastrointestinal tract and the thymus. A cardiopulmonary safety study was conducted 
in female beagle dogs. Based on all of the data collected in this study, there was no 
evidence of cardiopulmonary pharmacological adverse effects of TP-0903 following a 
single, oral dose up to 2.0 mg/kg [14]. 
1.2 Rationale 
TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the 
mesenchymal phenotype associated with advanced cancers. TP-0903 has 
demonstrated profound single agent activity in CLL B-cells taken directly from patients 
even if the patient has high risk factors (ie, 17p/P53 deletions) or progressed on other 
agents (ie, ibrutinib). TP-0903 is currently being evaluated in patients with refractory 
solid tumors (TP-0903-101). This proposed study is designed to identify the maximum 
tolerated dose (MTD), safety profile and recommended Phase 2 dose (RP2D) of 
TP-0903 when administered orally once daily for 28 days on a 28-day cycle to patients 
with previously treated CLL. Treatment cycles may be repeated if the patient continues 
to show benefit and if TP-0903 is reasonably well tolerated. 
 
 


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2. 
DRUG INFORMATION – TP-0903 
A comprehensive review of TP-0903 is contained in the Investigator’s Brochure 
provided by the Sponsor. This document should be reviewed prior to initiating the 
study. 
2.1 Background 
TP-0903 is a potent biochemical inhibitor of AXL kinase, part of the TAM family of 
RTKs. AXL was originally cloned from patients with chronic myeloid leukemia. When 
overexpressed, it exhibits transforming potential. AXL overexpression has been 
reported in a variety of cancers including pancreatic cancer, colon cancer, thyroid 
carcinoma, breast cancer and hematological malignancies [3]. AXL is constitutively 
active in CLL and TP-0903 demonstrated strong activity at targeting these cells 
compared to normal cells. 
2.2 Chemistry 
To date, the drug substance utilized in the preparation of the drug product was 
a mono-tartrate salt (Form B). In a second drug product manufacturing 
campaign, the same drug substance was used, but the 4-mg and 16-mg 
strengths were packaged into color-coded capsules. Results from additional 
development work on the TP-0903 drug substance including testing multiple 
tartrate salt polymorph forms for solubility, stability, reproducibility upon 
preparation and other physical attributes, as well as toxicology and 
pharmacokinetics, identified a more suitable, di-tartrate form of the drug 
substance, Form A, which has been selected for future clinical use. The 
polymorph forms tested all exhibited similar solubility, toxicity, and 
pharmacokinetics characteristics compared to the drug substance used in the 
current clinical form of TP-0903 (Form B). The di-tartrate salt form of TP-0903 
that was selected was based on reproducibility compared to the current clinical 
form.  
A summary of important chemical characteristics of both drug substance forms 
is presented in Table 1. 


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Table 1. 
Nomenclature and Notable Chemical Characteristics of 
Both Clinical Drug Substance Forms (B and A) 
Chemical 
Characteristic
Clinical Drug Substance  
(Form B) 
Clinical Drug Substance 
(Form A)  
(free base:tartaric acid ratio of 1:2) 
Chemical Name 
(IUPAC) 
{[5-chloro-2-({4-[{4-
methylpiperazin-1-
yl)methyl]phenyl} 
amino)pyrimidin-4-yl]amino}-N,N-
dimethylbenzene-1-sulfonamide 
mono-tartrate salt 
{[5-chloro-2-({4-[{4-
methylpiperazin-1-
yl)methyl]phenyl} 
amino)pyrimidin-4-yl]amino}-N,N-
dimethylbenzene-1-sulfonamide 
di-(L)-tartrate salt 
Other Names 
TP-0903, TP0903, HCI-2084, 
CCS-1589/STG-08, TP-0903 
tartrate 
TP-0903, TP0903,  
CDS-0051/STG-08, TO5, TP-0903 
di-tartrate 
Description 
White to off-white powder 
Off-white to yellow- to brown-
colored powder 
Chemical 
Formula 
C28H36ClN7O8S 
C32H42ClN7O14S 
Molecular 
Weight 
666.15 Daltons 
816.23 Daltons 
Structural 
Formula 
 
 
 
2.3
Drug Description
Study drug is supplied as 1-, 4-, 16-, 25-, and 100-mg doses in hard, gelatin capsules 
(size #3 for the 1-, 4-, 16-, and 25-mg doses; size #0 for the 100-mg dose) that are 
manufactured under current clinical Good Manufacturing Practices (cGMP) for 
investigational use.  
2.4 Mechanism of Action 
The observed mechanism of action of TP-0903 in cells and in preclinical animal 
models is consistent with AXL kinase being the dominant pharmacological target. AXL 
belongs to the family of RTKs called the TAM receptors. This family includes AXL, 
TYRO3, and MER. The TAM receptors are defined by a combination of 
2 immunoglobulin-like domains and dual fibronectin type III repeats in the extracellular 
region of the protein [15]. Two ligands, GAS6 and protein S have been identified for 
the TAM receptors [3]. These ligands are vitamin K-dependent proteins that exhibit 
43% amino-acid sequence identity and share domain structures. 


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Inhibition of AXL signaling by a dominant-negative receptor mutant (AXL-DN) 
suppresses experimental gliomagenesis, migration, and invasion, and leads to 
long-term survival of mice after intracerebral glioma implantation compared with AXL 
wild-type transfected tumor cells [16]. Additionally, AXL is detected at higher levels in 
metastases or malignant tumors compared to normal tissues or primary tumors, and 
a higher level is associated with a poor clinical outcome [4, 5]. AXL can also exist as 
a soluble molecule (sAXL), which is generated by ADAM10-mediated proteolysis and 
is associated with GAS6 in the blood. The biological function of sAXL has not been 
well characterized; however, GAS6 in circulation can bind to sAXL rendering it 
incapable of stimulating the AXL receptor [17]. 
More recently, the role of AXL in tumorigenesis has focused on its regulation of a 
process called epithelial-to-mesenchymal transition (EMT). In EMT, epithelial cells 
lose their adhesion-dependence and become more migratory, invasive, and generally 
more resistant to treatment, all of which are properties of mesenchymal stem cells. 
Epithelial-to-mesenchymal transition is a natural process required for embryonic 
development and wound healing; however, the same process is utilized by cancer 
cells to initiate metastasis and enable drug resistance. Targeting the EMT process has 
been hypothesized as a potential strategy to suppress the spread of cancer to both 
neighboring and distant tissues and to sensitize cancer cells to standard-of-care 
treatments. Due to the central role of AXL in regulating EMT, it has emerged as an 
important therapeutic target, especially for tumor types that rely heavily on EMT for 
drug resistance. 
AXL was identified as a potential therapeutic target in CLL by studying the interaction 
between CLL B-cells and bone marrow stromal cells (BMSC). It was found that CLL 
utilizes microvesicles to constitutively activate AXL signaling in both the diseased 
B-cells and the associated BMSCs [8]. 
2.5 Preclinical Studies 
2.5.1 
In Vitro Pharmacology 
TP-0903 was designed to be a potent and selective inhibitor of AXL kinase. In a 
biochemical kinase assay, TP-0903 inhibited the activity of AXL kinase with an 
inhibitory concentration in 50% of test subjects (IC50) of 12 nM. A number of additional 
biochemical assays have been performed to determine the in vitro potency of TP-0903 
against other protein kinases. In addition to AXL kinase, TP-0903 shows potent 
inhibition of several other protein kinases in the low nanomolar range in these 
biochemical assays, including MER and TYRO3. 
2.5.1.1 TP-0903 effects on Gas6-induced epithelial-to-mesenchymal 
transition (EMT) 
The mesenchymal phenotype in many cancer cells is central to the pathogenesis of 
tumors. Increased AXL expression in tumor cells is strongly associated with enhanced 
chemoresistance, proliferation, and migration, each of which are features of the 
mesenchymal phenotype. In order to investigate the on-target effects of TP-0903, the 
compound was tested in cell migration assays stimulated by the cognate ligand of 
AXL, GAS6. TP-0903 completely inhibited migration of AsPC-1 cells in this EMT 
dependent migration assay. TP-0903 also decreased the expression of mesenchymal 


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cell markers, such as Slug and Snail, in cells from hematological cancers and solid 
tumors. 
2.5.1.2 Effect of TP-0903 on GAS6/AXL-dependent Phospho-signaling 
Pathways 
To determine the on-target effects of TP-0903 on downstream signaling from AXL 
kinase, an enzyme-linked immunosorbent assay (ELISA) using the Meso Scale 
Discovery platform was used to detect the phosphorylation of AKT, following AXL 
stimulation with GAS6. Indicated cell lines were serum-starved for 4 hours, treated 
with TP-0903 for 2 hours, and stimulated with GAS6 for 10 minutes. TP-0903 inhibited 
GAS6-mediated induction of phospho-AKT in a concentration-dependent manner in 
3 different cell lines, confirming that TP-0903 inhibits AXL kinase in cultured cancer 
cells (Figure 1). 
 
Figure 1 
TP-0903 Inhibits GAS6/AXL-mediated Phospho-AKT 
Activity 
2.5.1.3 Antiproliferative Activity in Cancer Cells 
TP-0903 was evaluated for its in vitro anticancer efficacy against a panel of cultured 
cancer cell lines. The IC50 values observed ranged from 0.0145 μM to 0.205 μM. The 
greatest sensitivity was observed in the A549 lung carcinoma cell line (Table 2). 


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Table 2 Activity of TP-0903 in Human Cancer Cell Lines 
Cell Line 
Cell Type 
TP-0903, IC50 (μM) 
A549 
Lung carcinoma 
0.0145 
H1650 
Lung carcinoma 
0.0699 
Panc-1
Pancreatic carcinoma 
0.078 
HL-60 
Acute promyelocytic leukemia 
0.205 
MV4-11 
Acute myeloid leukemia 
0.0586 
2.5.1.4 Effect of TP-0903 on CLL B-cells 
AXL was found to be overexpressed and constitutively active in CLL B-cells taken 
directly from patients (Figure 2) [18]. The CLL B-cells from 2 different patients showed 
overexpression of AXL compared to T-cells from the same patients. Additionally, 
normal B-cells from a healthy volunteer did not have elevated AXL expression. 
Furthermore, 10 CLL patients (including P1 and P2) were evaluated for AXL 
activation/phosphorylation (P-AXL) and total AXL expression by western blot analysis. 
Seven of the 10 patients showed high AXL activation. 
 
Figure 2
AXL Overexpression and Activation in CLL B-cells 
Taken Directly from Patients 
TP-0903 has been extensively evaluated against CLL B-cells taken directly from CLL 
patients. In 20 CLL samples from low-risk patients, TP-0903 had an average EC50 of 
inducing apoptosis between 125 to 175 nM. Similarly, in 18 CLL samples from 
high-risk patients, the average EC50 was around 150 nM (Figure 3) [6]. 


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Figure 3
TP-0903 Potently Induces Apoptosis in CLL Cells 
Regardless of Risk Factors
 
Similar activity was observed in CLL B-cells co-cultured with BMSCs with no effect on 
the viability of the BMSCs (Figure 4) [6]. Typically, BMSCs provide a protective niche 
that shelters CLL B-cells from the therapeutic effect of drugs. TP-0903 appears to 
overcome this protective niche and demonstrates potent activity in this co-culture 
environment. 
 
Figure 4
TP-0903 Potently Targets CLL B-cell Viability Even in the 
Presence of BMSCs 
 


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To determine if the induction of apoptosis from TP-0903 treatment correlated with the 
inhibition of AXL, CLL B-cells were treated with TP-0903 and AXL activation was 
determined by western blot (Figure 5) [6]. TP-0903 down-regulates the 
phosphorylation and activation of AXL in CLL cells, which is consistent with the 
observed strong apoptotic response, regardless of CLL risk category. 
 
Figure 5
TP-0903 Potently Targets AXL Signaling in CLL B-cell, 
which Correlates with the Induction of Apoptosis 
(Cleaved Caspase3) 
 
An additional, independent study separate from the studies listed above demonstrated 
TP-0903 is very active (IC50 <500 nM) in CLL cells acquired from patients exposed to 
or progressed on ibrutinib (Figure 6) [19] and other targeted agents. 
 
Figure 6
Induction of Apoptosis by TP-0903 in Lymphocytes from 
CLL Patients Before (Week 0) and After (Weeks 1, 4 and 
12) Ibrutinib Therapy (3 Samples from Single Patient) 


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2.5.2
In Vivo Pharmacology 
2.5.2.1 Single Agent Activity in Tumor-bearing Animal Models 
The in vivo efficacy of TP-0903 was evaluated using 2 xenograft tumor models, the 
MV4-11 AML model and the A549 lung carcinoma model. All tumor models were 
implanted subcutaneously in the hind flank of the athymic nude mice. Tumor volumes 
were allowed to grow to a medium size (approximately 100 mm3) before stratification 
and initiation of dosing. General health, tumor volumes, and body weights were 
followed over the course of the study. In both xenograft models, TP-0903 caused 
regression in starting tumor sizes without any adverse effects on body weights 
(Figure 7). 
 
Figure 7 
Tumor Growth Reduction in Leukemia and Lung 
Carcinoma Mouse Xenograft Models  
 
2.5.3
Safety Pharmacology 
A number of assays were performed to evaluate the potential effects of TP-0903 on 
hERG activity. 
2.5.3.1 Effects on hERG Channel Function 
Biochemical binding to the hERG channel was evaluated using the Predictor™ hERG 
Fluorescence Polarization Assay (Invitrogen). Results showed that TP-0903 is a weak 
biochemical inhibitor of hERG activity, exhibiting an IC50 greater than 1 μM. In addition, 
3 separate hERG patch-clamp experiments were also conducted, 2 using HEK-293 
cells [20, 21] and 1 using CHO cells [11]. The data from cell-based Study No. 191081 
suggests that TP-0903 inhibits hERG activity by greater than 50% at 1 μM in 
transfected HEK-293 cells. However, data from the 2 other patch-clamp assays 
conducted in both HEK-293 and CHO cells are more consistent with the data from the 


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cell-free biochemical screen, concluding that hERG inhibition is not significant (>50%) 
below 1 μM of TP-0903. 
2.5.3.2 Receptor Panel Screening 
TP-0903 was screened through the “Safety 44 panel” of safety-associated receptors 
and enzymes offered by Cerep [11]. TP-0903 inhibited only 15 of these assays when 
screened at the highest dose tested at 10 μM. Based on animal pharmacokinetic data, 
animal efficacy models and toxicology data, 10 μM concentrations have not been 
reached in animals and are not expected to be achieved in future human studies. 
Therefore, off-target receptor inhibition is not expected to lead to significant toxicity 
concerns in future testing of TP-0903. 
2.5.3.3 Cardiovascular Safety Assessment in Dogs 
Tolero sponsored a study to examine the potential toxicity and toxicokinetics of 
TP-0903 when administered orally to dogs for 28 consecutive days as well as the 
progression or regression of any effects following a 14-day treatment-free recovery 
period (Nucro-Technics Study No. 302456) [12].  
Electrocardiograms (ECGs) (6 limb leads) were obtained for all animals once during 
the pretreatment period and on Day 27 of dosing at approximately 1.5 hours postdose; 
close to the time to Cmax (peak time) (Tmax) (2 hr ±30 minutes). Tracings were assessed 
for gross changes indicative of cardiac electrical abnormalities. Heart rate (HR) (lead 
II), rhythm or conduction abnormalities were also evaluated. Each ECG was evaluated 
for HR, rhythm, P wave duration, QRS duration, PR interval, and QT duration. The 
morphology of the QRS complexes was evaluated in the frontal plane leads for gross 
abnormalities. ECGs were evaluated by a Board-certified Veterinary Cardiologist. 
Blood pressure (BP) using a noninvasive technique was recorded at approximately 
the same time as ECGs, and included HR, and systolic/diastolic BP. 
The HR, PR interval, P wave duration, and QRS duration were within normal limits for 
all groups and there was no significant difference noted between groups at the different 
time points. The QT interval was within normal limits for all groups and all time points. 
Prestudy HR was significantly lower in the high dose group compared to all other 
groups and was considered an incidental finding. No arrhythmias were noted in the 
different groups at the different time points. 
2.5.4 
Nonclinical Absorption, Distribution, Metabolism and 
Excretion Studies 
2.5.4.1 Drug Transporter Effects 
TP-0903 was tested in a bidirectional cell permeability assay using confluent 
monolayer of Caco-2 cells in a 96-well based format. Fenoterol, Propranalol, and 
Digoxin were used as controls. The efflux ratio (mean apparent permeability [Papp] A 
to B / mean Papp B to A) for TP-0903 was determined to be 1.49. Although mass 
recovery was low, this data suggests that TP-0903 is not a substrate for P-glycoprotein 
and is a compound of moderate permeability. 


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2.5.4.2 CYP450 Effects 
TP-0903 was evaluated for the inhibition of human cytochrome P450 (CYP) isozymes 
using human liver microsomes in the presence of NADPH. At 10 μM, TP-0903 
inhibited the activity of only isoform 2C19 by more than 50% out of the isozymes 
selected for testing. The IC50 values were determined against all the CYP isozymes 
used in the panel and, consistent with the percent inhibition data, only 2C19 was 
inhibited at a concentration lower than 10 μM (IC50 4.4 μM).  
2.5.4.3 Liver Microsome Stability Studies 
The stability of TP-0903 in the presence of isolated microsomes from 3 species 
(human, rat and dog) were determined. The concentration of TP-0903 was measured 
by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with reference to a 
standard curve. The t1/2 of TP-0903 ranged from 4.3 minutes in humans to 4.9 minutes 
in dogs. 
2.5.4.4 Metabolite Profile and Identification 
To identify potential first-pass metabolites, TP-0903 was incubated in the presence of 
human hepatocytes for 2 hours and the composition of the resulting mixture of 
compounds was determined by LC-MS/MS. Following the 2-hour incubation, 55% of 
the parent compound remained and 7 metabolites were observed. The 3 major 
metabolites result from demethylation of the dimethyl sulfonamide (M3) or N-Methyl 
piperazine (M4) and oxidation (M7). The proposed metabolites are shown in Figure 8. 
 


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Figure 8 Identified Metabolites of TP-0903 Exposed to Human 
Hepatocytes 
2.5.4.5 Serum Albumin Binding 
The serum albumin binding levels for TP-0903 were determined using human plasma 
in a dialysis plate-based assay. The free fraction of TP-0903 was measured by 
LC-MS/MS, by reference to a standard curve, and warfarin was used as a control. 
Data showed that TP-0903 has moderate human serum albumin binding (7% 
unbound). Recovery of protein bound drug (80.3 %) indicated the binding was 
reversible. 
N
N
N
N
HN
N
H
Cl
S
N
O
O
TP-0903,  MW = 515.2
Oxygenation
N
N
N
N
HN
N
H
Cl
S
N
O
O
O
Glucuronidation
M7,  MW = 531.2
M1,  MW = 707.2
N
N
HN
N
Cl
S
N
O
O
M5,  MW = 415.1
Dealkylation
Demethylation
N
N
N
N
HN
N
H
Cl
S
H
N
O
O
N
NH
N
N
HN
N
H
Cl
S
N
O
O
M4, MW = 502.2
M6,  MW = 517.2
Oxygenation
M3,  MW = 502.2
Demethylation
Demethylation
N
NH
N
N
HN
N
H
Cl
S
H
N
O
O
M2,  MW = 488.2
Demethylation
N
N
N
N
HN
N
H
Cl
S
H
N
O
O
O


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2.5.4.6 pKa of TP-0903 
The pKa values for TP-0903 were determined by titration using ultraviolet metric 
detection. The pKa was determined in aqueous buffer and separately in the presence 
of 2 cosolvents (80% methanol and 60% DMSO). The final pKa values were calculated 
as an average of the 3 values obtained under different solvent conditions with the 
exception of pKa 3, for which the pKa value determined in DMSO was excluded. The 
final pKa values for pKa1, pKa2, and pKa3 were 3.02, 3.96, and 7.81, respectively. 
2.5.4.7 pH-dependent Solubility of TP-0903 
The equilibrium solubility of TP-0903 tartrate was determined in the following media: 
pH 3.5, 4.5, 5.5, 6.5 USP buffers, 0.1N HCl, SGF, fasted state simulated intestinal 
fluid, and fed state simulated intestinal fluid. As expected, based on the pKa 
determination, TP-0903 showed greatest solubility in acidic media. 
2.5.5 
Animal Toxicology and Pharmacokinetics 
2.5.5.1 Rat Studies 
2.5.5.1.1 
7-day Repeated Oral Dose Range-finding Study of TP-0903 
with Single and Repeated Dose PK in Rats (Study No. 
293892) 
A 7-day repeated oral dose range-finding study of TP-0903 with single and repeated 
dose pharmacokinetics (PK) was performed in rats [22]. Groups of 4 male and 
4 female rats received 2, 4, or 8 mg/kg of TP-0903 dissolved in 1% Tween 80 / 5% 
D-Į-tocopherol polyethylene glycol 1000 succinate (TPGS) / water (v/v/v) by oral 
gavage once daily for 7 consecutive days followed by a 7-day observation period.  
Analysis of all generated data, clinical observations, body weight, body weight 
changes, food consumption, clinical pathology evaluations, gross necropsy, and organ 
weights revealed that dose levels of TP-0903 at 2 and 4 mg/kg/day administered orally 
once a day for 7 days were well tolerated in both males and female rats. The plasma 
levels and exposure (based on area under the plasma concentration curve [AUC] from 
time 0 to 12 hours (AUC0-12) displayed a linear increase with dose following a single, 
3 and 7 days of dosing at 2 and 4 mg/kg/day with higher exposures in females 
compared to males and plasma levels that did not change during treatment. 
At a dose of 8 mg/kg, male rats tolerated the 7 day repeated doses of TP-0903 well 
and plasma concentrations of TP-0903 did not change during treatment. In contrast, 
female rats treated orally with TP-0903 at 8 mg/kg/day showed treatment-related 
toxicity including decreased food consumption, weight loss, pallor, diarrhea, and 
melena. The most prominent hematological finding at the end of treatment was a 
reduction of white blood cells associated with severe neutropenia. The main findings 
in gross necropsy for the female rats that were moribund sacrificed on Day 8 were 
spleen enlargement, renal pallor, and bone marrow as well as reduction of abdominal 
fat and muscle mass (cachexia). Plasma concentrations of TP-0903 in female rats at 
a dose of 8 mg/kg were higher compared to male rats and much higher on Day 7 
compared to Day 3 indicative of a dose accumulation effect. 


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Pharmacokinetic studies of TP-0903 revealed a rapid absorption with Tmax values 
similar, between male and female rats, across all doses and days of dosing, ranging 
from 0.5–2.0 hrs. The magnitude of the plasma AUC from time 0 to the time of the last 
concentration (AUC0-Tlast) displayed a gender bias, being approximately 1.5-2-fold 
higher in females compared to males, with the only exception being high dose females 
following 7 days of dosing where the AUC0-Tlast was 5.8-fold higher. Maximum 
observed plasma concentration (Cmax) and AUC0-Tlast dropped slightly with increasing 
days of dosing, with the exception of high dose females where AUC0-Tlast did not 
change from Day 1 to Day 3 and increased from Day 3 to Day 7 by approximately 
2-fold. Following a single dose and 3 days of dosing the AUC0-12 increased in a linear 
fashion between doses for both male and female rats. On the seventh day of dosing, 
the relationship between increasing dose and AUC0-12 deviated from linearity in female 
rats, due to a larger than expected increase of the high dose AUC0-12 suggesting that 
there was dose accumulation of TP-0903. 
2.5.5.1.2 
28-day Repeated Oral Dose Toxicity and Toxicokinetic 
Study of TP-0903 in Rats (Study No. 302457) 
The potential toxicity and toxicokinetics of TP-0903 when administered orally to rats 
daily for 28 days was evaluated [13]. Groups of 10 male and 10 female rats received 
0.5, 2, or 4 mg/kg/day of TP-0903 dissolved in 1% Tween 80 / 5% TPGS / water (v/v/v) 
by 
oral 
gavage 
once 
daily 
for 
28 consecutive 
days. 
A 
control 
group 
(10 males/10 females) was dosed with the vehicle only. The progression or regression 
of any effects were evaluated during an additional 14-day treatment-free period in the 
control group and in rats dosed at 2 and 4 mg/kg/day.  
There were no treatment-related observations recorded during the 28 days of dosing 
or 14-day treatment-free period in the control group. Mean body weights and mean 
body weight gains of the male rats in the high dose group were significantly lower at 
the end of treatment; however, this was not observed in the females of this group. 
The main finding of toxicological relevance in the hematology evaluations was a slight 
reduction of reticulocyte counts in the high dose group which may reflect reduced 
erythropoiesis. This finding appeared to be transient since reticulocyte counts in the 
high dose recovery group were comparable to the control group. Coagulation, serum 
chemistry, and urinalysis evaluations did not reveal any test item treatment-related 
findings. 
TP-0903 was rapidly absorbed following oral administration, with the majority of the 
Tmax values between 1–2 hrs in both males and females. There was no evidence of 
dose accumulation observed on Days 1, 15, and 28 of dosing. Females had higher 
Cmax values than males at all doses and on all days of dosing but there were no 
differences in the Tmax values and the higher Cmax values in females were not 
associated 
with 
differences 
in 
clinical, 
clinical 
pathology 
and 
anatomo-
histopathological findings. The elimination half-life (t1/2(e)), determined from the 
available data of dose groups of 2 and 4 mg/kg ranged from 2.3-8.9 hours and was 
similar in both genders. TP-0903 exhibited a high volume of distribution suggesting for 
a large tissue distribution. 


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There were no gross findings of toxicological relevance observed in gross necropsy 
examinations performed at the end of treatment and recovery periods. The only finding 
of possible toxicological relevance in the organ weight evaluation was a lower weight 
of thyroid with parathyroids in male rats dosed with the test item; however, there were 
no abnormal findings in the histopathology of thyroid and parathyroids.  
The abnormalities found in histopathology of the high dose rats included small acute 
hemorrhages in mesenteric lymph nodes in 5 animals and focal inflammatory infiltrates 
and/or focal lobular atrophy in pancreas of 3 control and 7 high dose animals. These 
findings were equivocal and it could not be determined whether they were related to 
test item treatment. While exposure to the test item had a dose-related effect on the 
body weight of male rats in the high dose group and was associated with a transient 
mild reduction in erythropoiesis in males and females, no underlying mechanism of 
action was apparent from the histopathology evaluations. Hematopoiesis evaluated in 
the spleen and bone marrow tissues were similar in the high dose and control groups. 
Based on all data generated, including clinical observations, body weights, food 
consumption, ophthalmoscopy, clinical pathology, toxicokinetics, gross pathology and 
histopathology, the No Observed Adverse Effect Level (NOAEL) of TP-0903 following 
28 days of repeated oral dosing in rats was determined to be 2 mg/kg/day. 
2.5.5.2 Dog Studies 
2.5.5.2.1 
Single Oral Dose and 7-Day Repeated Oral Dose Toxicity 
and Pharmacokinetic Study of TP-0903 in Dogs (Study No. 
294865) 
This study established a dose level by a single oral dose (Part A) and determined the 
toxicity and PK of TP-0903 (Part B) dissolved in 1% Tween 80 and 5% vitamin-E TPGS 
in water following 7 days of repeated oral dosing in Beagle dogs [23]. Doses were 
administered via a stomach tube at a dose volume of 2 mL/kg after overnight fasting. 
Food was offered approximately 1 hour after dosing. 
Three groups of dogs, each consisting of 1 male and 1 female, received a single 
TP-0903 dose of 0.25, 0.5, or 1 mg/kg and observed for 14 days (Part A). Salivation 
was observed in the high dose (1 mg/kg) male dog approximately 30 minutes 
postdose. Emesis was observed in the high dose female dog approximately 
60 minutes postdose. All dogs completed the treatment period and survived the 
scheduled observation period. There were no other observations of toxicological 
relevance seen in hematology and serum chemistry evaluations.  
In Part B of the study, 3 groups of dogs, each consisting of 2 males and 2 females, 
received TP-0903 for 7 consecutive days at doses of 0.25, 0.75, or 1.25 mg/kg/day 
followed by 7-day observation period. A control group comprised of 1 male and 
1 female received vehicle only.  
All dogs completed the treatment and observation periods and survived to scheduled 
necropsy. Analysis of all generated data, including clinical observations, body weights, 
food consumption, clinical pathology, gross necropsy, and organ weights revealed no 
test article treatment-related significant toxicity in dogs that were treated orally with 


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TP-0903 up to 1.25 mg/kg/day for 7 days. Clinically, TP-0903 caused emesis at the 
initial dose level of 0.25 mg/kg/day and up to 1.25 mg/kg/day. 
Pharmacokinetic studies of TP-0903 revealed a rapid absorption with Tmax values 
similar between male and female dogs, across all doses and days of dosing, ranging 
from 0.5–6.0 hours. The magnitude of the plasma AUC0-Tlast did not display a gender 
bias. Oral t(1/2)e and mean residence time (MRT) values were slightly longer following 
7 days of dosing. The AUC0-Tlast increased linearly with dose across genders and 
following a single and 7 days of dosing. At the doses employed, there was little 
evidence of dose accumulation for TP-0903 in Beagle dogs following 7 days of 
repeated dosing. 
2.5.5.2.2 
Seven-day, Three Times Per Day, Repeated Oral Dose 
Toxicity and Pharmacokinetic Study of TP-0903 in Dogs 
(Study No. 298717) 
This study evaluated the toxicity and pharmacokinetics of TP-0903 following 7 days of 
3 times a day, repeated oral dosing in dogs [24]. This study was performed following 
the 7-day repeat dose, once a day repeat dose study (Study No. 294865) to support 
the determination of the MTD of TP-0903 in dogs.  
To achieve sufficient systemic exposure at the high dose levels, 2 groups of 2 females 
were dosed with TP-0903 incorporated in gelatin capsules at dose levels of 3 or 
6 mg/kg/day (1 or 2 mg/kg/dose).  
In the 3 mg/kg/day dose group, both dogs had emesis on most of the dosing days with 
the vomiting time ranging from approximately 15 minutes to 2 or 6 hours postdose. 
Soft feces or diarrhea was observed from Days 3 or 7 to 14. One of the dogs had a 
1.1 kg body weight loss over the 7-day treatment period and started to regain body 
weight, gaining 400 g, during the 7-day recovery period. The other dog gained 300 
and 600 grams body weight over the 7 and 14-day periods, respectively. 
Both dogs in the 6 mg/kg/day (2 mg/kg/dose î 3 days) dose group, showed various 
signs of toxicity early in the treatment phase. The severity of the clinical signs 
increased, and the health condition of the dogs deteriorated after each subsequent 
dose. The clinical signs mostly consisted of vomition, diarrhea, emaciation, anorexia, 
dehydration, apathy, and weight loss. Due to deteriorating health, the 2 dogs in this 
group were dosed only twice a day on Day 4 and dosing was skipped on Days 5 and 
6, but the dogs were dosed for the PK evaluation on Day 7. After the end of treatment, 
the condition of animals continued to deteriorate, and their condition did not improve 
despite support with fluid therapy provided on Day 9. One dog was found dead the 
morning of Day 10 and the second dog was euthanized in moribund condition that 
same day. 
Clinical pathology results in the dogs dosed at 6 mg/kg/day, on Day 8, showed slight 
increases in white blood cells (WBCs), red blood cells (RBCs) and neutrophils; 
increased hematocrit and hemoglobin values; and decreased reticulocyte counts in 
one of the dogs. In the other dog, there were increases in WBCs, RBCs, neutrophils, 
monocytes, and basophils; increased hematocrit and hemoglobin values; and 
decreased reticulocyte counts and platelets. 


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In the dogs dosed at 3 mg/kg/day, on Day 8, all hematology parameters were within 
the normal ranges for of the dogs. In the second dog there was a slight increase in 
RBC count; increased hematocrit and hemoglobin values; and reticulocyte count, 
although within the normal range, was decreased compared to the pretreatment count. 
On Day 14, hematology results were within the normal reference ranges with exception 
of a slight increase in reticulocyte counts in 1 of the dogs of this group. The only serum 
chemistry parameters that were affected in the dogs dosed at 3 mg/kg/day were 
elevated ALT (almost twice the normal upper limit) in 1 of the dogs and elevated 
triglycerides in both dogs.  
Pharmacokinetic analysis revealed that the plasma exposure to TP-0903 as measured 
by AUC from time 0 to infinity (AUC0-inf) was not dose proportional and higher on Day 7 
compared to Day 1 following the third dosing, and even more so for the 6 mg/kg/day 
dose compared to the 3 mg/kg/day dose. These observations were made despite the 
vomiting that occurred and a partial cessation of dosing at the 6 mg/kg/day dose, 
suggesting that there may be a tendency for dose-accumulation following consecutive 
days of dosing. Cmax values were minimally impacted while Tmax values were longer at 
the 6 mg/kg/day dose. Both the t(1/2)e and MRT values were slightly longer with 
increased days of dosing suggesting a change in the clearance mechanisms for 
TP-0903 with consecutive days of dosing. 
Necropsy was performed on the dogs that were unscheduled sacrificed and found 
dead on Day 10. At necropsy, cachexia and dark yellowish and watery lower intestinal 
contents were observed in 1 dog. In the other dog, cachexia, hyperemia of the 
glandular portion of the stomach; hemorrhagic lower intestines and rectum; dark 
reddish black color of lower intestinal contents; and hyperemia in the cortex and 
medulla of the kidneys were observed. 
The MTD of TP-0903 was reached following dosing of 1 mg/kg/dose 3 times per day 
(3 mg/kg/day) and the dogs recovered well within 1 week of cessation of treatment.  
2.5.5.2.3 
28-Day Repeated Oral Dose Toxicity Study of TP-0903 in 
Beagle Dogs followed by a 14-Day Recovery Period 
(Study No. 302456) 
This study examined the potential toxicity and toxicokinetics of TP-0903 when 
administered orally to dogs for 28 consecutive days [12]. The progression or 
regression of any effects following a 14-day treatment-free recovery period was also 
assessed. Two groups of dogs (3 males/3 females) were dosed with TP-0903 
incorporated in gelatin capsules at the following dose levels: 0.1, 0.5 mg/kg/day for 
28 days and another group was dosed at 1 mg/kg/day for the first 14 days, followed 
by 2 mg/kg/day for the remaining 14 days of the treatment period. A control group of 
dogs was included in the study and was dosed with empty gelatin capsules.  
All dogs completed the 28-day treatment period and survived until scheduled 
termination for necropsy. Clinical signs noted in the high-dose group during the 
treatment period included vomition, salivation, diarrhea, and/or soft feces. Vomition 
affected all dogs in the high-dose group and was observed in some dogs in the 
mid-dose group. Reduced food consumption was observed in 1 male and 1 female; 
whereas weight loss was observed in 1 out of 5 males and 2 out of 5 females in the 


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high-dose groups during Weeks 3 and/or 4 of treatment and following the dose 
increase from 1 mg/kg to 2 mg/kg. These signs were not observed at the end of the 
recovery period. 
There were no ophthalmoscopy findings at the end of treatment in any of the animals. 
Evaluation of clinical pathology data (hematology, coagulation, serum chemistry, and 
urinalysis) did not reveal any findings clearly attributable to the test item.  
TP-0903 resulted in a dose-dependent increase in plasma concentrations. TP-0903 
was quantified in some plasma samples following dosing at 0.1 mg/kg, however most 
plasma concentrations were below the lower limit of quantitation (0.2 ng/mL). The dose 
proportionality and linearity of plasma concentrations of TP-0903 following oral dosing 
could not be well characterized given the low plasma levels at the lowest dose. 
However, a comparison of the mid and high doses suggests that plasma 
concentrations in male and female dogs increased approximately in a dose 
proportional manner. At both the mid and high doses, all predose levels of TP-0903 
were below the limit of quantification and for the high dose, the elimination half-lives 
were similar on all days of dosing, suggesting a lack of dose accumulation. The 
analysis of toxicokinetic data revealed a high clearance of TP-0903 in plasma that was 
caused from a large volume of distribution suggesting that TP-0903 was well 
distributed in tissues. 
Gross pathology findings observed in a few animals in the high-dose group included 
hemorrhage in colon of 3 animals and cecum of 1 animal, as well as hyperemia in the 
pylorus in 1 dog and hyperemia in the rectum in another dog. The hemorrhages were 
likely agonal, but might indicate recent injury to the mucosa. No gross findings were 
observed in recovery animals in the high- and mid-dose groups. 
There were no apparent differences in absolute and relative organ weights between 
the control group and test item groups (both genders) with the exception of a few 
incidental significant differences: higher mean weights of thyroids with parathyroids in 
the low-dose males and an increase in the mean weights for uterus sizes in Group 4 
females, due to physiological luteal phase with endometrial hypertrophy. 
Histopathological findings of possible toxicological significance included changes in 
the thymus and the lower gastrointestinal tract tissues. 
x 
Thymic atrophy was found at the end of the treatment period in 3 out of 6 high-
dose animals, 3 out of 6 mid-dose animals, 1 out of 6 low-dose animals, and 1 
out of 6 control animals. This finding was also noted in 2 of 4 dogs in both the 
high- and mid-dose groups at the end of the recovery period. Thymic atrophy 
is a physiological response to stress and an expected finding in young dogs 
around the onset of sexual maturity, so these findings are considered to be 
nonspecific and indirectly related to the treatment-associated gastrointestinal 
effects. 
x 
Minimal or mild degree of mucosal injury and inflammation in the small intestine 
were observed at the end of the treatment period in 1 mid-dose dog, 
4 high-dose dogs, and 1 dog in the control group. At the end of the recovery 
period, 1 control dog, 1 mid-dose dog, and 2 high-dose dogs had similar mild 


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residual changes. The small intestinal mucosal injury associated with the 
high-dose regimen was considered to have returned to background level at the 
end of the 14-day recovery period. 
x 
At the end of the treatment period, minimal or mild degree of mucosal injury 
and inflammation in the colonic mucosa was observed histologically in four 
animals in the high-dose group. These responses were characterized by 
increased amounts of cell debris in a few glands, associated with patchy 
neutrophil infiltrates, or focal areas of hemorrhage in the lamina propria. One 
control animal also had minimal injury to colonic glands without inflammation 
or hemorrhage. Similar findings were not observed in the large intestines in 
any of the animals of the mid-dose group. Minimal degeneration of the colon 
mucosal glands was observed at the end of the recovery period in 
one high-dose dog. 
Evaluation of clinical observations, body weight assessment, food consumption, 
ophthalmology, ECGs, clinical pathology, gross necropsy, and organ weights did not 
reveal any findings of clinical or toxicological relevance in dogs dosed at 
0.1 mg/kg/day. With the exception of vomiting, no other adverse findings of 
toxicological significance were found in dogs dosed with TP-0903 at 0.5 mg/kg/day. 
Emetogenic effect is a common finding observed in dogs dosed with kinase inhibitor 
drugs and could be attributed in part to a higher susceptibility of this species toward 
this class of drugs.  
Administration of TP-0903 at a dose of 1 mg/kg/day for 14 days, followed by 
2 mg/kg/day for 14 days was, for the most part, well tolerated by young male and 
female Beagle dogs used in this study. Emesis was the most obvious adverse effect 
occurring in this dose group and was more pronounced upon the dose increase to 
2 mg/kg. Other clinical signs, including salivation, diarrhea or soft feces and reduction 
of body weight gains, were observed during the third and/or fourth weeks of treatment. 
Upon the ceasing of treatment, there were no clinical signs observed in the recovery 
animals. Histopathological findings indicated that the potential target organs of toxicity 
were the lower gastrointestinal tract and thymus. Upon completion of the treatment 
period, there were no clinical signs or histopathological findings observed in the 
recovery animals with the exception of thymic atrophy which was considered to be a 
stress-related nonspecific response and may have occurred during the treatment 
phase. 
2.6 Clinical Studies 
This is the second Phase 1 study of TP-0903 in humans, but the first in patients with 
a hematologic malignancy. Most of the toxicology findings observed with TP-0903 in 
preclinical drug safety studies were typical of antiproliferative compounds, including 
bone marrow (ie, neutropenia, thrombocytopenia, and anemia) and gastrointestinal 
effects (ie, vomiting, diarrhea, anorexia). Observations were largely reversible during 
the recovery period. They are not uncommon for anticancer agents and are expected 
to be manageable and/or reversible in the clinic. 


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2.7 Justification for Study Treatment Plan and Starting Dose 
The starting dose was based on a thorough review of both the rat and dog GLP 
toxicology studies, as well as preliminary results from the ongoing Phase 1 study in 
patients with advanced metastatic or progressive solid tumors (Study No. 
TP-0903-101). TP-0903 was administered orally once each day for 28 days in the GLP 
toxicology studies. In the rat, all findings were reversible or felt not to be clinically 
significant and the NOAEL was determined as 2 mg/kg or 12 mg/m2. Based on the 
animal toxicology and safety studies, the starting dose for TP-0903-101 was 
1.5 mg/m2/day. However, given the clinical experience now acquired in this solid tumor 
study and the lack of dose-limiting toxicities (DLTs) observed in any of the first 
6 cohorts, the proposed starting dose for TP-0903 in Group 1 (monotherapy) will be a 
25-mg flat dose. The starting dose will be approximately one dose level below the 
current Phase 1a solid tumor study. Group 2 patients (combination therapy) will start 
at one dose level below Group 1, or a 20-mg flat dose, to ensure safety particularly 
with the combination of ibrutinib and TP-0903. The use of a flat, rather than body 
size-based dose, particularly for orally administered drugs, is preferable as it facilitates 
the use of the drug by patients and physicians and reduces the number of dosage 
strengths needed, improving compliance. 
Because TP-0903 has been well tolerated to date in the 101 solid tumor study, the 
proposed starting dose of 25 mg in the monotherapy arm is equivalent to 700 mg 
(25 PJî  GD\V RU  RIWKH FXUUHQW GRVHLQ WKH  VROLGWXPRU VWXG\7KH
proposed starting dose in the combination arm (ie, TP-0903 plus ibrutinib) will be 
20 mg, which is a further 20% reduction from the 25 mg starting dose in the 
monotherapy arm. Tolero believes that the available safety information from the 101 
solid tumor study, together with the lower starting doses suggested in this study, 
support the proposed continuous, 28-day dosing schedule. 
2.8 Summary of Risk and Benefits 
TP-0903 is a new inhibitor of AXL kinase that has shown promising preclinical activity 
against a variety of both hematological and solid tumor malignancies. Preclinical 
studies suggest that bone marrow, gastrointestinal tract, and the thymus may be 
potential target organs of toxicity. In the rat, reticulocyte counts were reduced; 
however, these findings were not observed in the dog. In the dog, minimal to mild 
injury to the mucosal lining as well as inflammation was noted in the small intestines 
and colonic mucosa. Thymic atrophy was also noted in the dog. With the exception of 
vomiting, no other adverse effects of significance were observed in the dog. The 
preclinical GLP toxicology studies suggest that the observed toxicities were reversible 
following a recovery period of 14 days with the exception of thymic atrophy. 
As of 03 August 2018, 23  patients over 7 different dose cohorts have been 
treated with TP-0903 in the ongoing Phase 1 solid tumor study, TP-0903-101. No 
DLTs had been reported. National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) Grade 3 and 4 events that occurred in one patient 
each included anemia, hypocalcemia, hypokalemia, hyponatremia, pleural 
effusion, urinary tract infection, ascites, hyperkalemia, hypertension, bacterial 
peritonitis, sciatica, and syncope. None of these events was considered study 
drug-related. The most common Grade 1 and 2 AEs (ie, those that occurred in 
SDWLHQWVHDFK>@LQFOXGHGQDXVHDYRPLWLQJIDWLJXHDQHPLDGLDUUKHD


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hypoalbuminemia, decreased appetite, hypomagnesemia, tachycardia, and 
WKURPERF\WRSHQLD*UDGHDQG$(VWKDWRFFXUUHGLQSDWLHQWVHDFK
and judged as at least ‘Possibly’ related to TP-0903 included diarrhea, nausea, 
vomiting, dysgeusia, and thrombocytopenia. There were no serious adverse 
events (SAEs) considered related to study drug or deaths on study to date. 


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3. 
STUDY OBJECTIVES 
Phase 1 
Primary Objectives: 
x 
To characterize the safety and toxicity profile of TP-0903 when administered 
orally once daily for 28 days (each cycle is 28 days; no drug-free period) in the 
following patient groups: 
o Group 1 (TP-0903 monotherapy): those with CLL/SLL who are 
intolerant to, or have had progressive disease on B-cell receptor 
antagonists,  BCL-2 antagonists or other investigational treatments for 
CLL/SLL   
o Group 2 (TP-0903 and ibrutinib combination therapy): those with 
CLL/SLL who have progressed on ibrutinib, yet the treating provider 
considers continuation of ibrutinib therapy to be in the best interest of 
the patient   
x 
To determine the RP2D of TP-0903 when administered orally on this schedule 
to the defined patient groups 
Secondary Objectives: 
x 
To observe patients for any evidence of antileukemic activity of oral TP-0903 
by determining the Objective Response Rate ([ORR], ie, rate of complete 
response [CR] plus rate of partial response [PR] in the defined patient groups 
according to guidelines set forth by the 2018 International Workshop on CLL 
(IWCLL)  
x 
To evaluate the pharmacokinetics (PK) of oral TP-0903 in the defined patient 
groups 
Exploratory Objective: 
x 
To study potential biomarkers relevant to disease and  pharmacodynamics 
(PD) of oral TP-0903 in the defined patient groups through assessment of 
analytes including, but not limited to, soluble AXL, AXL expression and 
phosphorylation, growth arrest specific 6 (GAS6), and mesenchymal 
transcription factors in peripheral blood samples and bone marrow 
Phase 2 
Primary Objective: 
x 
To determine the ORR in the two defined patient groups according to 
guidelines set forth by the 2018 IWCLL 
Secondary Objectives: 
x 
To determine the Duration of Response (DoR, ie, the time from tumor response 
to disease progression) 


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x 
To determine the Progression-free Survival (PFS, ie, the time from first dose 
to objective tumor progression or death) 
x 
To determine the rate of Overall Survival (OS, ie, the time from first dose to 
death from any cause) 
Exploratory Objective: 
x 
To study potential biomarkers relevant to disease and  pharmacodynamics 
(PD) of oral TP-0903 in the defined patient groups through assessment of 
analytes including, but not limited to, soluble AXL, AXL expression and 
phosphorylation, growth arrest specific 6 (GAS6), and mesenchymal 
transcription factors in peripheral blood samples and bone marrow 
 
 


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4. 
INVESTIGATIONAL PLAN 
4.1 Overall Study Design 
This is a combined Phase 1/2 study of oral TP-0903 in patients with previously treated 
CLL/SLL. In both Phase 1 and Phase 2, study participants will be assigned to 1 of 
2 groups: 
x 
Group 1 (TP-0903 monotherapy): Patients who are intolerant to, or have had 
progressive disease on B-cell receptor antagonists and/or BCL-2 antagonists 
or other investigational treatments  
x 
Group 2 (TP-0903 and ibrutinib combination therapy): Patients who have 
progression of disease on ibrutinib and the treating provider considers 
continuation of ibrutinib therapy to be in the best interest of the patient. 
Both groups of patients will be treated identically with TP-0903 and will undergo the 
same study assessments. The study is expected to take up to 36 months to enroll up 
to 108 patients (up to 27 patients in each group  (Group 1 and Group 2) in both Phase 
1 (n=54) and Phase 2 (n=54). A schematic representation of the study design is 
provided in Figure 9. 
Phase 1 
Patients will be enrolled in Group 1 and Group 2 in cohorts of 3 to 6 patients 
simultaneously. Group 2 will start at 1 dose level below the group 1 starting dose. In 
each group, escalation of the TP-0903 dose will follow a standard 3+3 design with 
sequential cohorts of 3 patients treated with incrementally higher doses of TP-0903 
until a DLT is observed and the MTD is established. Once the first patient at a dose 
level is enrolled, the second and third patients will be enrolled after 3 weeks if the initial 
patient has not experienced a DLT or any unacceptable toxicity. 
If 1 of 3 patients in a cohort experiences a DLT, up to 3 additional patients will be 
treated at that dose level. If no additional DLTs are observed in the expanded 3- to 
6-patient cohort within 28 days after the last patient was first dosed, the dose will be 
escalated in a new cohort of 3 patients. If 2 or more of 3 to 6 patients at a given dose 
level experience a DLT during the first cycle, then the MTD will have been exceeded 
and up to a total of 6 patients will be treated at the previous lower dose level. If 0 or 1 
of 6 patients experiences a DLT at this previous lower dose level, this dose will be 
declared the MTD. 
7KH07'LVGHILQHGDVWKHGRVHDWZKLFKRISDWLHQWVH[SHULHQFHD'/7GXULQJ
Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a 
DLT during Cycle 1. Once the MTD or preliminary RP2D is identified, an expansion 
cohort of up to six patients will be enrolled in each patient group to confirm 
safety/confirm the suitability of the preliminary RP2D, to collect additional biomarker 
data, and to further explore efficacy. 
It is expected that up to 27 patients will be enrolled in each patient group for a total of 
up to 54 patients in Phase 1. 


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Additional dose levels, schedules or disease indications of TP-0903 may be explored, 
as appropriate, based on the modulation of key biomarkers, the safety profile and 
clinical signals of activity. 
Phase 2 
In Phase 2, patients will be enrolled in Group 1 and Group 2 based on the Simon 
2-stage design. In Stage 1, up to 13 patients will be enrolled into each patient group 
(total of 26 patients). If there are zero responses among these 13 patients in each 
group, the study will be stopped. Otherwise, Stage 2 will open to enroll 14 additional 
patients in each group for a total of 27 patients per group. If 4 or more responses are 
observed among 27 patients, the conclusion will be that the study treatment is worthy 
of further investigation. When the true response rate of 20% (alternative hypothesis) 
is tested against the null hypothesis response rate of 5%, this design yields a Type I 
error rate of 0.05 and power of 80%. 
If both patient groups enroll through Stage 2, it is anticipated that the total enrollment 
for Phase 2 will be 54 patients. 
Any patient who withdraws from the study for treatment-related toxicity prior to being 
evaluated for response in Phase 2 will be considered a nonresponder. Patients who 
drop out of the study for other reasons prior to being assessed for response will be 
considered unevaluable and may be replaced. Enrollment in either patient group may 
EHVWRSSHGDWDQ\SRLQWRQFHSDWLHQWVKDYHKDGDUHVSRQVHWRWUHDWPHQWEXWWKH
maximum enrollment in each patient group in Phase 2 will be 27 evaluable patients. 
 


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MTD: maximum tolerated dose; RP2D: recommended Phase 2 dose 
Figure 9 
Study Design Schema 
 


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4.2 Assignment to Treatment 
This is an open-label study; randomization and blinding will not be performed as per 
this study design. All patients will receive TP-0903 either alone or in combination 
according to the group into which they are enrolled in the Phase 1 part of the study, 
and subsequently in Phase 2 at the RP2D dose identified from Phase 1. 
Patients will be enrolled from all participating centers. The study will be managed by 
the Sponsor and/or its designee and all sites must receive authorization from the 
Medical Monitor for enrollment of any eligible patient. 
4.3 Patient Population 
4.3.1 
Number of Patients 
A sufficient number of patients will be treated to establish the MTD of TP-0903 (up 
to 54 patients) in the Phase 1 part of the study and then up to 54 additional patients 
in Phase 2. Any patient who withdraws from the study before completing the Cycle 1 
Day 28 assessments will be replaced unless that patient is withdrawn due to toxicity 
or has experienced a DLT. 
Any patient who withdraws from the study for treatment-related toxicity prior to being 
evaluated for response in Phase 2 will be considered a nonresponder. Patients who 
drop out of the study for other reasons prior to being assessed for response will be 
considered unevaluable and may be replaced. Enrollment in either patient group 
PD\EHVWRSSHGDWDQ\SRLQWRQFHSDWLHQWVKDYHKDGDUHVSRQVHWRWUHDWPHQWEXW
the maximum enrollment in each patient group in Phase 2 will be 27 evaluable 
patients. 
4.3.2 
Inclusion Criteria 
To be eligible for participation, patients must meet all of the following inclusion 
criteria: 
1. 
%H\HDUVROG 
2. 
Have an established, pathologically confirmed diagnoses of CLL/ Small 
Lymphocytic Lymphoma (SLL) requiring therapy according to the 2018 
IWCLL guidelines  
3. 
Have received at least one prior therapy for CLL/SLL and can be classified 
in one of two patient groups: 
x 
Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who are 
intolerant to, or have progressed on B-cell receptor antagonists 
and/or BCL-2 antagonists or 
x 
Group 2 (TP-0903 and ibrutinib combination therapy): Patients with 
CLL/SLL who have progression of disease on ibrutinib and the 
treating provider considers continuation of ibrutinib therapy to be in 
the best interest of the patient 
4. 
Have an Eastern Cooperative Oncology Group (ECOG) performance status 
 


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5. 
Have adequate hematologic function: 
x 
$EVROXWHQHXWURSKLOFRXQW$1&500/μL 
x 
Platelet count 30,000/μL 
x 
Hemoglobin  g/dL in the absence of transfusions within the 
previous 2 weeks  
6. 
Have adequate organ function: 
x 
Creatinine clearance 0 mL/min 
x 
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
OHYHO2.5 îXpper limit of normal (ULN) 
x 
+DYHDWRWDOELOLUXELQOHYHOî8/1XQOHVVVHFRQGDU\WR*LOEHUW
syndrome, hemolysis, or leukemia) 
7. 
Have acceptable coagulation status: 
x 
Activated partial thromboplastin (aPTT) and prothrombin time (PT) 
5 î8/1 
8. 
Have a negative pregnancy test (if female of childbearing potential) 
9. 
Be nonfertile or agree to use an adequate method of contraception. Sexually 
active patients and their partners must use an effective method of 
contraception (hormonal or barrier method of birth control, or abstinence) 
prior to study entry and for the duration of study participation and for at least 
30 days after the last study drug dose. Should a woman become pregnant or 
suspect that she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
10. 
Have read and signed the Institutional Review Board (IRB)-approved 
informed consent form (ICF) prior to any study related procedure. (In the 
event that the patient is rescreened for study participation or a protocol 
amendment alters the care of an ongoing patient, a new ICF must be signed.) 
11. 
Be able to comply with the requirements of the entire study 
4.3.3 
Exclusion Criteria 
Patients meeting any 1 of these exclusion criteria will be prohibited from participating 
in the study.  
1. 
Have undergone prior autologous or allogeneic stem cell transplant within 
PRQWKV KDYH Qot recovered from transplant associated toxicities, or 
requires graft versus host immunosuppressive therapy 
2. 
Have known central nervous system (CNS) involvement 
3. 
Have Richter’s transformation of CLL  
4. 
Have received any monoclonal antibody therapy directed at treatment of 
the patient’s malignancy within 2 weeks prior to anticipated first dose 


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5. 
Have 
received 
any 
anticancer 
therapy 
including chemotherapy, 
radiotherapy, or an investigational anticancer drug within less than 
5 half-lives of the last dose of that treatment 
x 
This exclusion criterion is not applicable to patients requiring 
continuation on ibrutinib. (Note: Certain patients with a rapidly rising 
white blood cell count while on ibrutinib may need to remain on this 
drug for medical reasons. These patients will need to be approved by 
the Medical Monitor and treated in accordance with the protocol.) 
7. 
Have a corrected QT interval of >450 msec (males) and >470 msec 
(females) using Fridericia’s correction formula 
8. 
Have a significant history of renal, neurologic, psychiatric, endocrinologic, 
metabolic, immunologic, hepatic, or cardiovascular disease or any other 
medical condition that, in the opinion of the Investigator, would adversely 
affect his/her participation in the study 
9. 
Are pregnant and/or nursing, or refuse to use appropriate contraceptives 
during the course of the study and for at least 30 days after the last dose 
of study drug 
10. 
History of another malignancy in the last 5 years except for the following 
adequately treated: 
x 
Local basal cell or squamous cell carcinoma of the skin 
x 
Carcinoma in situ of the cervix or breast 
x 
Papillary, noninvasive bladder cancer 
x 
Early stage prostate cancer for which observation is clinically 
indicated  
x 
Other Stage 1 or 2 cancers currently in complete remission 
x 
Any other cancer that has been in complete remission for 2 years or 
surgically cured  
Medical Monitor may be contacted for additional determination of 
acceptable prior cancer history 
 
11. 
Have known gastrointestinal disorders (eg, malabsorption syndrome), 
complications (eg, dysphagia), or surgery that could make consumption or 
absorption of oral medications problematic 
12. 
Have an uncontrolled systemic infection (viral, bacterial, or fungal) or fever 
and neutropenia within 7 days prior to anticipated first dose 
13. 
Have active and uncontrolled autoimmune cytopenias for 2 or more weeks 
including autoimmune hemolytic anemia or idiopathic thrombocytopenic 
purpura (ITP) 
6. 
Have received >20 mg/day of prednisone and 0.1 mg/day of 
mineralocorticoids within 7 days prior to anticipated first dose 


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14. 
Have received prior therapy with an AXL inhibitor 
15. 
Have exhibited allergic reactions to a similar structural compound, 
biological agent, or formulation 
16. 
Are unwilling or unable to comply with procedures required in this protocol 
17. 
Have a history of severe adverse reaction (eg, hypersensitivity reaction, 
anaphylaxis) to sulfonamides 
4.4 Study Treatment 
This is a combined Phase 1/2 open-label study to investigate the safety, 
pharmacokinetics, pharmacodynamics, and clinical activity of TP-0903 in CLL 
patients. All patients enrolled in Group 1 will receive TP-0903 alone. All patients 
enrolled in Group 2 will receive TP-0903 and ibrutinib in combination. 
Phase 1 
Group 1 (TP-0903 monotherapy): The starting dose for TP-0903 in Group 1 
(monotherapy) will be a 25-mg flat dose. The study drug will be administered orally 
once daily for 28 days (each cycle is 28 days; no drug-free period). 
Patients may continue to receive TP-0903 in 28-day cycles at the same dose given 
during Cycle 1 until they experience unacceptable toxicity or unequivocal disease 
progression. No intrapatient escalation of the TP-0903 dose is permitted. 
Group 2 (TP-0903 in combination with ibrutinib): The starting dose of TP-0903 
will be a 20-mg flat dose. TP-0903 will be administered orally once daily for 28 days 
(each cycle is 28 days; no drug-free period). Patients will also receive ibrutinib at the 
same dose that they were receiving immediately prior to study enrollment. 
Patients should continue with the combination of ibrutinib and TP-0903 for at least 
3 months after study start. After that time, patients can either continue with 
combination therapy or discontinue ibrutinib and continue with TP-0903 
monotherapy at the discretion of the Investigator and in consultation with the Medical 
Monitor. Patients may continue to receive TP-0903 in 28-day cycles at the same 
dose given during Cycle 1 until they experience unacceptable toxicity or unequivocal 
disease progression.  
Ibrutinib may be stopped and reinitiated at the discretion of the Investigator and in 
consultation with the Medical Monitor; however, the total time patients may receive 
treatment with ibrutinib is 2 years. 
Phase 2 
Group 1 (TP-0903 monotherapy): The starting dose will be the RP2D determined 
during Phase 1. TP-0903 will be administered orally once daily for 28 days (each 
cycle is 28 days; no drug-free period). 
Dosing with TP-0903 may continue until a patient experiences unacceptable toxicity 
or unequivocal disease progression 


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Group 2 (TP-0903 in combination with ibrutinib): The starting dose will be the 
RP2D determined during Phase 1. TP-0903 will be administered orally once daily for 
28 days (each cycle is 28 days; no drug-free period). Patients will also receive 
ibrutinib at the same dose that they were receiving immediately prior to study 
enrollment. 
Patients should continue with the combination of ibrutinib and TP-0903 for at least 
3 months after study start. After that time, patients can either continue with 
combination therapy or discontinue ibrutinib and continue with TP-0903 
monotherapy at the discretion of the Investigator and in consultation with the Medical 
Monitor. Patients may continue to receive TP 0903 in 28-day cycles at the same 
dose given during Cycle 1 until they experience unacceptable toxicity or unequivocal 
disease progression.  
Ibrutinib may be stopped and reinitiated at the discretion of the Investigator and in 
consultation with the Medical Monitor; however, the total time patients may receive 
treatment with ibrutinib is 2 years. 
4.4.1 
TP-0903 Administration 
TP-0903 is administered orally once daily for 28 days (each cycle is 28 days; no 
drug-free period). Dosing may be repeated every cycle in the absence of disease 
progression or unacceptable toxicity. Study drug should be taken in the morning after 
an overnight fast with up to 200 mL or 7 fluid ounces of water at least 1 hour before 
ingesting any food or other medications. 
4.4.2 
Ibrutinib Administration 
Administer ibrutinib orally once daily at approximately the same time each day. 
Swallow the capsules whole with water. Do not open, break, or chew the capsules. 
4.4.3 
Description of Phase 1 and Phase 2 Parts of Study 
4.4.3.1 Phase 1 
Evaluation of the safety and toxicity profile and determination of RP2D of TP-0903 
will occur in Phase 1. The starting dose for TP-0903 in Group 1 (monotherapy) will 
be a 25-mg flat dose. Enrollment will be in cohorts of 3 to 6 patients using a standard 
3+3 design for dose escalation until the MTD is established. The starting TP-0903 
dose in Group 2 (TP-0903 combination therapy with ibrutinib) will be a 20-mg flat 
dose.  
Once the first patient at a dose level is enrolled, the second and third patients will be 
enrolled after 3 weeks as long as the initial patient has not experienced any 
unacceptable toxicity. Once the last patient enrolled has completed Day 28 without 
observation of a DLT and the next higher TP-0903 dose level has not yet been 
studied, the dose will be increased following a modified Fibonacci dose escalation 
scheme in a new 3- to 6-patient cohort according to the dose levels provided in 
Table 3 


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Table 3 TP-0903 Proposed Dose Escalation 
Dose 
Level 
Proposed Daily 
Dose 
Increment from 
Previous Dosea 
No. of Patients 
Per Cohort 
Group 1 (Monotherapy) 
1 
25 mg 
Starting Dose 
3-6 
2 
33 mg 
33% 
3-6 
3 
45 mg 
36% 
3-6 
4 
58 mg 
29% 
3-6 
5 
75 mg 
29% 
3-6 
 6b 
100 mg 
33% 
3-6 
Group 2 (Combination) 
1 
20 mg 
Starting Dose 
3-6 
2 
25 mg 
25% 
3-6 
3 
33 mg 
33% 
3-6 
4 
45 mg 
36% 
3-6 
5 
58 mg 
29% 
3-6 
6 
75 mg 
29% 
3-6 
 7b 
100 mg 
33% 
3-6 
a 
It is possible for additional and/or intermediate dose levels to be added during the course of 
the study. 
b 
If clinically indicated, dose levels higher than 100 mg may be investigated. 
 
If 1 of 3 patients in a cohort experiences a DLT, up to 3 additional patients will be 
treated at that dose level. If no additional DLTs are observed in the expanded 3- to 
6-patient cohort within 28 days after the last patient was first dosed, the dose will be 
escalated in a new cohort of 3 patients. If 2 or more of 3 to 6 patients at a given dose 
level experience a DLT during the first cycle, then the MTD will have been exceeded 
and up to a total of 6 patients will be treated at the previous lower dose level. If 0 or 
1 of 6 patients experiences a DLT at this previous lower dose level, this dose will be 
declared the MTD. 
7KH07'LVGHILQHGDVWKHGRVHDWZKLFKRISDWLHQWVexperience a DLT during 
Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a 
DLT during Cycle 1. 
Once the MTD or preliminary RP2D is identified, an expansion cohort of 
approximately six patients will be enrolled in each patient group to confirm 
safety/confirm the suitability of the preliminary RP2D, to collect additional biomarker 
data, and to further explore efficacy, and to further explore efficacy. 


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4.4.3.2 Phase 2 
In Phase 2, patients will be enrolled in each group (TP-0903 monotherapy and 
combination therapy with ibrutinib) at the RP2D based on the Simon 2-stage design. 
Stage 1 
In Stage 1, for both patient groups (monotherapy and combination therapy), up to 
13 patients with previously treated CLL will be enrolled and treated at the RP2D 
identified in the Phase 1 portion. If there are zero responses among these 
13 SDWLHQWVWKHVWXG\ZLOOEHVWRSSHG,IWKHUHDUHUHVSRQGHUVDGGLWLRQDOSDWLHnts 
will be enrolled in Stage 2. 
Stage 2 
In Stage 2, 14 additional patients will be enrolled for a total of 27 patients in each 
patient group (monotherapy and combination therapy). If 4 or more responses are 
observed among 27 patients, the conclusion will be that the study treatment is worthy 
of further investigation. If both patient groups enroll through Stage 2, it is anticipated 
that the total enrollment for Phase 2 will be 54 patients. 
4.4.4 
Missed Doses 
It is important that patients keep track of their study drug administration, including 
any missed doses (whether due to oversight or illness [ie, vomiting]). 
Regardless of cohort assignment, should a patient vomit after taking their TP-0903 
dose, they should not attempt to retake the dose, but rather note the dose as being 
missed in their Patient Dosing Diary (Appendix I) and continue with regular dosing 
on the next day. 
Patients cannot miss more than 4 doses of either TP-0903 or ibrutinib during Cycle 1 
and the missed doses must not be on 4 consecutive days or the patient will be 
replaced. 
If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as 
possible on the same day with a return to the normal schedule the following day. 
Extra capsules of ibrutinib should not be taken to make up for the missed dose [27].  
4.5 Management of Toxicities and Dosage Modification 
4.5.1 
Management of Toxicities 
AEs may be treated with concomitant medications, as deemed clinically indicated by 
the Principal Investigator. All concomitant medications must be recorded in the 
source and on the appropriate electronic case report form (eCRF). 
AEs that are moderate to severe in intensity (see Appendix D) for NCI-CTCAE 
toxicity grading) and considered Possibly, Probably, or Definitely related to study 
drug treatments may result in the termination of study treatment in the affected study 
patient. Such termination should be reviewed with the Sponsor’s Medical Monitor at 
the earliest possible time (Section 8.5). Following review with the Sponsor’s Medical 
Monitor, the study patient may be permanently withdrawn from the study depending 
upon the nature and severity of the event. 


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4.5.2 
Dose-limiting Toxicities 
A DLT is defined as any one of the following events observed within Cycle 1, 
regardless of attribution unless clearly and incontrovertibly related to the underlying 
disease or extraneous causes (such as progressive disease; other decreases in 
the white blood cell count, or in circulating granulocytes, are not to be 
considered, since a decrease in the white blood cell count is a desired 
therapeutic endpoint): 
x 
Any Grade  nonhematologic toxicity  
x 
Any Grade 3 AE WKDWGRHVQRWUHVROYHWR*UDGH1 within 72 hours with use 
of supportive care 
x 
$Q\$67DQG$/7HOHYDWLRQî8/1accompanied by serum bilirubin levels 
!î8/1 
x 
Any 
Grade 
3 
electrolyte 
disturbances 
(eg, 
hyperkalemia, 
hypophosphatemia, hyperuricemia) that do not resolve within <72 hours 
x 
Any *UDGHHOHYDWLRQVLQFUHDWLQLQH 
x 
Any Grade 5 toxicity 
x 
Any instance of febrile neutropenia 
4.5.3 
TP-0903 Dose Modifications 
The dose of TP-0903 will not be reduced during Cycle 1. Doses of study drug may 
be adjusted for patients who receive multiple cycles of TP-0903. Dose reductions by 
one dose level will be permitted based on the observed toxicity that occurred during 
the preceding cycle. No dose re-escalations will be allowed for any patient who had 
a previous dose reduction due to toxicity or delayed recovery. All dose modifications 
will need to be discussed and approved with the Medical Monitor.  
If a patient experiences toxicity, the patient may continue to receive TP-0903 as 
defined in Table 4 and in conjunction with the guidelines set forth by the 2018 
IWCLL Grading Scale for Hematologic Toxicity (Appendix C). 
Table 4 Guide to Dose Adjustments Based on Toxicities 
Drug-Related AE 
Action 
Grade 1 
Current dose level 
Grade 2 
Investigator’s option to reduce dose by 1 dose level with 
agreement of the Medical Monitor 
Grade 3a 
Withhold, then reduce dose by 1 dose level upon recovery to 
Grade 1 with agreement of the Medical Monitor. 
Grade 4 
Investigator and Medical Monitor review to determine if 
patient may continue on study with appropriate dose 
reduction upon recovery to Grade 1. 
a Excluding brief (based on the Investigator’s judgment) Grade 3 vomiting or diarrhea with suboptimal 
management. 
 


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Dose reduction to the next lower dose level tested will be performed initially. If further 
toxicities occur during 1 or more cycles at the new reduced dose level, no further 
reductions will be permitted, and the patient should be discontinued from the study. 
Patients who experience a DLT will be required to discontinue study participation, 
unless the Investigators and Medical Monitor determine that it is in the best interest 
of the patient to continue with the dose reduction and only upon recovery of the 
toxicity to Grade 2 or better. 
Dose reduction will be required for patients who have a delay in treatment greater 
than 2 weeks due to a lack of recovery of any hematologic or nonhematologic 
toxicity, even if DLT criteria are not met. Subsequent retreatment of patients who are 
not able to be treated after a 2-week delay and who eventually recover will be 
discussed between Investigators and Medical Monitor taking into account the 
potential benefit/risk for the individual patient. 
In addition, dose reductions will be permitted for patients who have toxicities that do 
not meet the criteria of a DLT and following discussion between the Investigator and 
the Medical Monitor. These toxicities will be discussed by the Investigators and 
Medical Monitor to determine if it would be in the best interest of the patient to 
continue to receive TP-0903 at the next previous dose level (Appendix D). 
4.5.4 
Ibrutinib Dose Modifications 
The package insert for ibrutinib therapy should be followed by the treating physician.  
As per the ibrutinib label [27]:  Interrupt ibrutinib therapy for any Grade 3 or greater 
non-hematological, Grade 3 or greater neutropenia with infection or fever, or Grade 4 
hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 
or baseline (recovery), ibrutinib therapy may be reinitiated at the starting dose. If the 
toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction 
of dose by 140 mg may be considered as needed. If these toxicities persist or recur 
following two dose reductions, discontinue ibrutinib. 
Recommended dose modifications are described below: 
 
Toxicity Occurrence 
CLL Dose Modification 
First 
+ROGLEUXWLQLEXQWLOUHFRYHU\WR*UDGHRUEDVHOLQH 
May restart at 420 mg daily 
Second 
+ROGLEUXWLQLEXQWLOUHFRYHU\WR*UDGHRUEDVHOLQH 
May restart at 280 mg daily 
Third 
+ROGLEUXWLQLEXQWLOUHFRYHU\WR*UDGHRUEDVHOLQH 
May restart at 140 mg daily 
Fourth 
Discontinue ibrutinib 
 
If ibrutinib is interrupted for a reason other than toxicity (eg, unrelated illness) the 
first instance of interruption must be restarted within 42 days. Subsequent study 
medication interruptions lasting more than 42 days, ibrutinib should be discontinued 
permanently. 


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4.6 Concomitant Medications and Therapies 
4.6.1 
Previous Therapies 
During Screening, patients will be asked about all previous therapies and all 
medications used during the previous 14 days from anticipated first dose. This 
information will be recorded in the source documentation and appropriate eCRF 
along with the diagnosis or reason for use. If a branded product is being taken, the 
generic name should be reported, if known. 
4.6.2 
Concomitant Therapies 
Concomitant therapies are any new or existing medications or therapy taken by the 
patient including: 
x 
Drugs, including but not limited to, prescription, over-the-counter, birth 
control pills/patches/hormonal devices, and homeopathic preparations 
x 
Nondrug therapies, including but not limited to, thermal/laser/radiation 
procedures, vitamins, herbal medicines/supplements. 
Once the patient receives the first dose of study drug, recording of concomitant 
therapies will be limited to any new medication or modification of an existing 
medication taken for treatment of an AE. These therapies will be recorded in the 
source documents and appropriate eCRF along with the diagnosis or reason for use. 
Those therapies used for the treatment of an AE are to be linked to an AE and 
documentation of the AE must also be completed (Section 8). 
If a branded product is being taken, the generic name should be reported, if known. 
4.6.2.1 Permitted Therapies 
Concomitant medications necessary for the health and well-being of the patient and 
that do not interfere with study assessments are permitted during the study at the 
Investigator’s discretion. This includes the use of appropriate medications for the 
treatment of AEs and/or concurrent illnesses under the direction of the Principal 
Investigator. All such therapies must be recorded in the source and on the 
appropriate eCRF. 
Treatment with hematopoietic colony stimulating growth factors such as granulocyte 
colony stimulating factor or granulocyte-macrophage colony stimulating factor may 
not be initiated during Cycle 1 unless the patient has experienced a DLT. Initiation 
of treatment with erythroid-stimulating agents may not occur during the first cycle of 
therapy. If a patient has been on a steady dose of an erythroid-stimulating agent, 
they may continue to use the agent at the same dose during Cycle 1 and later cycles. 


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Supportive Care Measures 
Supportive care will include: 
x 
Careful monitoring of patients at high risk for tumor lysis syndrome (TLS) (ie, 
SDWLHQWVZLWKDQ\O\PSKQRGH>/1@FPRUDEVROXWHO\PSKRF\WHFRXQW
>$/&@ î 109/DQGDQ\/1FP by collection of blood and real-time 
(STAT) review of TLS laboratory parameters (ie, uric acid, potassium, 
phosphate, calcium, and creatinine) on Day 1 of Cycle 1 at baseline 
(predose) and at 6 hours and 24 hours post dose.   
x 
Infection Prevention (ie, prophylactic antibiotic, antiviral, and/or antifungal 
therapy) to be initiated according to each institution’s standardized protocols 
4.6.2.2 Prohibited Therapies 
The following medications are excluded from concomitant use:  
x 
Anticancer therapies (chemotherapy, radiation therapy, immunotherapy) 
within less than 5 half-lives of the last dose of that treatment.  
o Note: Patients enrolled in Group 2 (TP-0903 in combination with 
ibrutinib) will continue treatment with the combination for at least 
3 months. Ibrutinib may be stopped and reinitiated at the discretion 
of the Investigator in consultation with the Medical Monitor; however, 
the total time patients may receive treatment with ibrutinib is 2 years. 
x 
CYP2C19 Metabolizers: Patients who are known abnormal metabolizers of 
CYP2C19 (ie, extensive or poor) prior to study treatment should be monitored 
closely. If possible, the Investigator should cease patient’s treatment with a 
CYP2C19 substrate prior to first dose, or at a minimum, switch to an 
alternative, but equivalent treatment that is not a CYP2C19 substrate 
(inhibitor or inducer). If a patient must remain on a CYP2C19 substrate, 
treatment with TP-0903 should proceed cautiously and the patient observed 
closely throughout the duration of the study.  
x 
Group 2 patients (ie, TP-0903 in combination with ibrutinib) should avoid 
coadministration 
of 
strong 
or 
moderate 
CYP3A 
inhibitors 
(eg, 
carbamazepine, rifampin, phenytoin, and St. John’s Wort) as these 
substances may increase ibrutinib plasma concentrations.  
x 
Group 2 patients should avoid coadministration of strong CYP3A inducers as 
these substances may decrease ibrutinib concentrations.  
x 
Patients must not be taking H2-receptor antagonists such as cimetidine, 
ranitidine, and famotidine, or any proton pump inhibitors such as omeprazole, 
lansoprazole, esomeprazole and pantoprazole. Patients must stop these 
medications within 7 days prior to starting treatment. 


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4.6.3 
Birth Control Requirements for Fertile Patients 
Sexually active patients and their partners must use an effective method of 
contraception associated with a low failure rate prior to study entry and for the 
duration of study participation and for 30 days after the last dose of study drug. The 
following are considered effective contraceptives: (1) oral contraceptive pill; (2) 
condom plus spermicide; (3) diaphragm plus spermicide; (4) abstinence; (5) patient 
or partner surgically sterile; (6) patient or partner more than 2 years 
postmenopausal; or (7) injectable or implantable agent/device. 
4.7 Protocol Deviations 
It is expected that this study will be conducted as described in this protocol, except 
for an emergency situation in which the protection, safety and well-being of the 
patient requires immediate intervention, based on the judgment of the Principal 
Investigator (or a responsible, appropriately trained and credentialed professional[s] 
designated by the Principal Investigator). In the event of a significant deviation from 
the protocol due to an emergency, accident, or error, the Principal Investigator or 
Designee must contact the Sponsor at the earliest possible time by telephone. This 
will allow an early joint decision to be made as to whether or not the patient should 
continue in the study. This decision will be documented in writing by both the 
Principal Investigator and the Sponsor. 
 
 


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5. 
ON-STUDY CLINICAL AND LABORATORY EVALUATIONS 
The Schedule of Assessments is outlined in Appendix A. These assessments apply 
to both the Phase 1 and Phase 2 portions of the study unless specified. 
5.1 Predose Assessments 
5.1.1 
Screening (Within 14 Days Prior to First Dose) 
The following procedures and evaluations will be performed within 14 days prior to 
administration of the first dose of study drug, after the ICF is signed unless otherwise 
noted: 
x 
Collect and document a complete medical history including histologically 
confirmed diagnosis of CLL/SLL 
o 1LJKWVZHDWVIRUPRQWKwithout evidence of infection 
x 
Record vital signs (body temperature, respirations, heart rate, blood 
pressure) 
x 
Assess ECOG Performance Status (Appendix B) 
x 
Evaluate laboratory parameters (Appendix E) 
o Full serum chemistry 
o Hematology (complete blood count [CBC] with differential and platelet 
count) 
o Coagulation parameters (PT and aPTT) 
o Urinalysis 
o Serum immunoglobulins 
o Direct antiglobulin 
o Serum ß2-microglobulin 
x 
Perform a 12-lead ECG including assessment of corrected QT interval (using 
Fridericia’s correction formula) (QTcF) 
x 
Pregnancy test (urine or serum beta-human chorionic gonadotropin 
pregnancy test for females of childbearing potential) 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements within the past 14 days 
o Perform a full physical examination, including height (cm) and weight (kg) 
and review the following constitutional symptoms suggestive of active 
disease: 
o 8QLQWHQWLRQDOZHLJKWORVVZLWKLQSUHYLRXV months 
o Marked fatigue 
o )HYHUV ) RU & IRU  ZHHNV ZLWKRXW HYLGHQFH RI
infection 


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x 
Assess baseline disease status per 2018 IWCLL guidelines (Appendix H) 
(within 28 days of Cycle 1 Day1): 
o Perform a computed tomography (CT) scan of neck, chest, abdomen, 
and pelvis for evaluation of lymphadenopathy, hepatomegaly, and 
splenomegaly;  
o Bone marrow biopsy and aspirate with matched peripheral blood 
sample 
o The following should be obtained (within 28 days of Cycle 1 Day 1): 
 
Molecular cytogenetics (FISH) for del(13q), del(11q), del(17p), 
add(12) [peripheral blood] 
 
Karyotyping with CpG (or institutional standard) stimulation 
[bone marrow] 
 
TP53 mutation analysis [peripheral blood] 
 
Immunoglobulin heavy-chain variable (IGHV) mutational analysis 
[peripheral blood] 
x 
Positron emission tomography (PET) scan to assess for possible Richter’s 
transformation (within 14 days of first dose) 
5.1.2 
Within 3 Days Prior to First Dose 
The following baseline procedures and evaluations will be performed any time within 
3 days (72 hours) prior to administration of the first dose of study drug (not required 
to be repeated at Cycle 1 Day 1 if screening exams are within 3 days prior to first 
dose): 
x 
Full physical examination, including weight (kg) 
x 
Record vital signs (body temperature, respirations, heart rate, blood 
pressure) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
o Pregnancy test (urine or serum beta-human chorionic gonadotropin 
pregnancy test for females of childbearing potential) 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 
x 
Review all inclusion/exclusion criteria and determine if patient has met all 
eligibility criteria for inclusion in the study. Obtain Medical Monitor (or 
designee) approval to enroll patient. See Study Manual for detailed 
instructions on procedures on enrollment. 


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5.2 Treatment Assessments 
5.2.1 
CYCLE 1 
5.2.1.1 Cycle 1: Day 1 
x 
Full physical examination, including weight (kg) 
x 
Record vital signs (temperature, respirations, heart rate, blood pressure) 
prior to first dose 
x 
Obtain baseline signs and symptoms prior to first dose 
x 
Assess ECOG Performance Status (Appendix B) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
o TLS labs to be assessed at baseline (predose) and at 6 hours and 
24 hours post dose (real-time [STAT] review) in patients at high risk 
IRU7/6LHSDWLHQWVZLWKDQ\/1FPRU$/& î 109/L and any 
/1 cm) 
o Pregnancy test (urine or serum beta-human chorionic gonadotropin 
pregnancy test for females of childbearing potential) 
x 
Perform 12-lead ECG just prior to first dose, including assessment of QTcF 
x 
Collect blood for analysis of PK parameters according to the schedule in 
Section 7.3 in Phase 1 only 
x 
Collect blood for exploratory biomarker assessments according to the 
schedule in Section 7.4 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 
5.2.1.2 Cycle 1: Daily on Days 1 through 28 
x 
Instruct patients to take TP-0903 and ibrutinib (for Group 2 patients) orally 
every day on Days 1 through 28 according to the guidelines detailed in 
Section 4.4.1 and Section 4.4.2 
x 
Instruct patients to record the date and time they took their dose(s) in their 
dosing diary (Appendix I) 


Protocol No. TP-0903-102 Amendment 2 
 
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5.2.1.3 Cycle 1: Weekly (Days 8, 15, and 22 [±3 Days]) 
Perform the following activities and evaluations weekly (or as otherwise indicated) 
during Cycle 1: 
x 
Perform an abbreviated physical examination (AE- or symptom-directed) 
x 
Record vital signs (temperature, respirations, heart rate, blood pressure) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
x 
On Day 8, collect blood for exploratory biomarker assessments according to 
the schedule in Section 7.4 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 
5.2.1.4 Cycle 1: Day 28 
x 
On Day 28, collect blood for analysis of PK parameters according to the 
schedule in Section 7.3 in Phase 1 only 
5.2.2 
CYCLE 2 
5.2.2.1 Cycle 2: Day 1 
x 
Full physical examination, including weight (kg) 
x 
Record vital signs (temperature, respirations, heart rate, blood pressure) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
o Pregnancy test (urine or serum beta-human chorionic gonadotropin 
pregnancy test for females of childbearing potential) 
x 
Assess ECOG Performance Status (Appendix B) 
x 
Perform 12-lead ECG just prior to dosing including assessment of QTcF 
x 
Collect blood for exploratory biomarker assessments according to the 
schedule in Section 7.4 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 


Protocol No. TP-0903-102 Amendment 2 
 
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5.2.2.2 Cycle 2: Daily on Days 1 through 28 
x 
Instruct patients to take TP-0903 and ibrutinib (for Group 2 patients) orally 
every day on Days 1 through 28 according to the guidelines detailed in 
Section 4.4.1 and Section 4.4.2 
x 
Instruct patients to record the date and time they took their dose(s) in their 
dosing diary (Appendix I) 
5.2.2.3 Cycle 2: Day 15 [±3 Days] 
x 
Perform an abbreviated physical examination (AE- or symptom-directed) 
x 
Record vital signs (temperature, respirations, heart rate, blood pressure) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 
5.2.2.4 Cycle 2: Day 28 (-4 Days) 
x 
Disease assessment – Assess for response per 2018 IWCLL guidelines 
(Appendix F): 
– 1LJKWVZHDWVIRUPRQWKZLWKRXWHYLGHQFHRILQIHFWLRQ 
o CT scan of neck, chest, abdomen, and pelvis evaluation of 
lymphadenopathy, hepatomegaly, and splenomegaly 
x 
If clinical and laboratory results indicate possible CR:  
o Collect bone marrow and aspirate with matched peripheral blood for 
CBC and determination of MRD (central lab assessment) 
o Review of the following constitutional symptoms suggestive of active 
disease: 
– 8QLQWHQWLRQDOZHLJKWORVVZLWKLQSUHYLRXV months 
– Marked fatigue 
– )HYHUV)RU&IRUZHHNVZLWKRXWHYLGHQFHRI
infection 


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5.2.3 
CYCLES 3 
Patients may continue to receive TP-0903 in 28-day cycles at the same dose given 
during Cycle 1 until they experience unacceptable toxicity or unequivocal disease 
progression. 
5.2.3.1 Cycles 3: Day 1 
Perform the following activities and evaluations on Day 1 of Cycle 3 and all 
subsequent cycles of treatment: 
x 
Full physical examination, including weight (kg) 
x 
Record vital signs (temperature, respirations, heart rate, blood pressure) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
o Pregnancy test (urine or serum beta-human chorionic gonadotropin 
pregnancy test for females of childbearing potential) 
x 
Assess ECOG Performance Status (Appendix B) 
x 
Perform 12-lead ECG just prior to dosing including assessment of QTcF 
x 
Collect blood for analysis of PK parameters according to the schedule in 
Section 7.3 in Phase 1 only 
x 
Collect blood for exploratory biomarker assessments according to the 
schedule in Section 7.4 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 
5.2.3.2 Cycles 3: Daily on Days 1 through 28 
x 
Instruct patients to take TP-0903 and ibrutinib (for Group 3 patients) orally 
every day on Days 1 through 28 according to the guidelines detailed in 
Section 4.4.1 and Section 4.4.2  
x 
Instruct patients to record the date and time they took their dose(s) in their 
dosing diary (Appendix I) 


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5.2.3.3 Cycles 3: Day 15 (±3 Days) 
Perform the following activities and evaluations during Cycle 3 and all subsequent 
cycles of treatment: 
x 
Perform an abbreviated physical examination (AE- or symptom-directed) 
x 
Record vital signs (temperature, respirations, heart rate, blood pressure) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 
5.2.3.4 
Cycles 3: Day 28 (-4 Days) 
Perform the following evaluations on Day 28 of every EVEN cycle (ie, Cycle 4, 
Cycle 6, etc): 
x 
Disease assessment – Assess for response per 2018 IWCLL guidelines 
(Appendix F): 
o Review of the following constitutional symptoms suggestive of active 
disease: 
– 1LJKWVZHDWVIRUPRQWKZLWKRXWHYLGHQFHRILQIHFWLRQ 
o CT scan of neck, chest, abdomen, and pelvis evaluation of 
lymphadenopathy, hepatomegaly, and splenomegaly 
x 
If clinical and laboratory results indicate possible CR:  
o Collect bone marrow and aspirate with matched peripheral blood for 
CBC and determination of MRD (central lab assessment) 
– 8QLQWHQWLRQDOZHLJKWORVVZLWKLQSUHYLRXV months 
– Marked fatigue 
– )HYHUV)RU&IRUZHHNVZLWKRXWHYLGHQFHRI
infection 


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5.3 End-of-Study Assessments 
If, at any time, a patient discontinues study treatment, a visit should be scheduled 
as soon as possible and within 14 days of the last dose of study drug or within 
14 days of the decision to discontinue study treatment. If the decision to withdraw 
the patient occurs at a regularly scheduled visit, that visit may become the End-of-
Study visit rather than having the patient return for an additional visit. 
x 
Perform a full physical examination including weight (kg) 
x 
Record vital signs (temperature, respirations, heart rate, blood pressure) 
x 
Evaluate laboratory parameters (Appendix E): 
o Full serum chemistry 
o Hematology (CBC with differential and platelet count) 
o Pregnancy test (urine or serum beta-human chorionic gonadotropin 
pregnancy test for females of childbearing potential) 
x 
Assess ECOG Performance Status (Appendix B) 
x 
Perform a 12-lead ECG including assessment of QTcF 
x 
Disease assessment LI  ZHHNV VLQFH ODVW DVVHVVPHQW – Assess for 
response per IWCLL guidelines 2018 (Appendix F). If patient has 
unequivocal evidence of disease progression, then this reassessment may 
be eliminated: 
o Review of the following constitutional symptoms suggestive of active 
disease: 
– 8QLQWHQWLRQDOZHLJKWORVVZLWKLQSUHYLRXV months 
– Marked fatigue 
– )HYHUV)RU&IRUZHHNVZLWKRXWHYLGHQFHRI
infection 
– 1LJKWVZHDWVIRUPRQWKZLWKRXWevidence of infection 
o CT scan of neck, chest, abdomen, and pelvis evaluation of 
lymphadenopathy, hepatomegaly, and splenomegaly 
x 
If clinical and laboratory results indicate possible CR:  
o Collect bone marrow and aspirate with matched peripheral blood for 
CBC and determination of MRD (central lab assessment) 
x 
Collect blood for exploratory biomarker assessments according to the 
schedule in Section 7.4 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 


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5.4 30-Day Safety Follow-Up Assessments 
Patients must undergo a safety evaluation in which the condition of the patient 
during the 30 days after the last dose of study drug can be assessed. There is a 
visit window of up to 14 days after completion of 30 days from the last dose 
(ie, within 45 days after last dose of study drug).The following assessments will 
be performed: 
x 
Assess for AEs 
x 
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements as well as antineoplastic 
therapies since discontinuation of study drug 
5.5 Long-term Follow-up for Patient Survival (Phase 2 only) 
All patients enrolled and treated in the Phase 2 study will be contacted by telephone 
to assess for date of death, date of relapse, or continued remission beginning the 
month after the patient completes the end-of-study assessments up to a maximum 
of 2 years regardless of how many cycles study treatment a patient receives. 
x 
Year 1: follow-up every month (± 7 days) 
x 
Year 2: follow-up every other month (± 14 days)  
 
 


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6. 
OFF-STUDY CRITERIA 
6.1 Withdrawal of Patients 
All patients have the right to withdraw at any time during treatment without prejudice. 
Circumstances may occur under which a patient may be permanently removed from 
the study. The criteria used to justify withdrawal of a study patient are described 
below. 
In the event of a premature withdrawal, the assessments for the End-of-Study visit, 
as detailed in the Schedule of Assessments (Appendix A), should be completed at 
the time of withdrawal, wherever possible, including dates of response and death. If 
the study patient is prematurely withdrawn due to an AE, attempts should also be 
made to clinically follow the study patient until the event is resolved, stable or 
permanent as determined by the Principal Investigator and Sponsor. 
6.2 Reasons for Withdrawal 
A patient may be permanently removed from the study for any of the following 
reasons: 
x 
Disease progression; 
x 
An excessive Grade 3-4 toxicity without a response to treatment or 
occurrence of any other AE, concurrent illness or laboratory abnormality 
which, in the opinion of the Principal Investigator, warrants the patient’s 
permanent withdrawal;  
x 
Patient noncompliance, defined as refusal or inability to adhere to the study 
schedule; 
x 
At the request of the patient, Principal Investigator, the Sponsor, or regulatory 
authority; 
x 
Patient is lost to follow-up;  
x 
Patient becomes pregnant while on study; 
x 
Patient begins another treatment for their disease; or 
x 
Patient death. 
6.3 Follow-Up for Patients Withdrawn from Study 
Patients withdrawn from the study with an ongoing AE must be followed clinically 
until the event is resolved, deemed stable, deemed permanent, or a new treatment 
for CLL is initiated as determined by the Principal Investigator and Sponsor. A stable 
AE is defined as an AE that is not expected to change in nature, severity, or 
frequency. See Section 8.4 through Section 8.8 for reporting of AEs. Patients 
withdrawn from the study for pregnancy will be followed according to Section 5.3 and 
Section 5.4. The pregnancy of any patient, or patient’s partner, will be followed to 
term to record any birth defects/abnormalities at time of birth. 


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6.4 Termination or Suspension of Study 
Should the Sponsor or their representatives, Investigators, or appropriate regulatory 
officials discover conditions during the study that indicate that the study or site 
involvement should be put ‘On Hold’ or ‘Terminated’, this action may be taken after 
appropriate consultation with the Sponsor, Investigators, and Study Monitors. 
Conditions that may warrant termination of the study or involvement of a study site 
include, but are not limited to: 
x 
If the Data Safety Monitoring Board (DSMB) recommends stopping the study 
due to safety concerns; 
x 
The discovery of an unexpected, serious, unacceptable risk to patients 
enrolled in the study; 
x 
Failure of the Investigator(s) to comply with pertinent clinical trial regulations; 
or 
x 
Insufficient adherence to protocol requirements. 
 
 


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7. 
CRITERIA FOR EVALUATION  
7.1 Safety Endpoints 
Phase 1 
Safety will be monitored from the time of the first dose until 30 days after the last 
dose of TP-0903. During Phase 1, the safety endpoints will be evaluated after 
Cycle 1. The dose escalation committee, comprised of Investigators, sponsor and 
CRO representatives, will have access to complete safety profiles of all patients 
receiving TP-0903 to enable decision making. 
The primary safety endpoint is to assess the tolerance and toxicity of continuous 
orally administered TP-0903 through evaluation of physical examinations, vital signs, 
laboratory parameters, solicited and unsolicited AEs including DLTs, and all causes 
of mortality up to 30 days from the last dose in both phases of the study. In Phase 2, 
all causes of mortality will also be evaluated at 60 days from the last administered 
dose. 
Overall safety profile will be characterized by type, frequency, severity, seriousness, 
timing, duration, and relationship of study drug to AEs and laboratory abnormalities. 
Treatment-emergent AEs (TEAEs), namely, AEs with initial onset or that worsen in 
severity after the first dose of TP-0903 will be classified using the Medical Dictionary 
for Regulatory Activities (MedDRA) v20.0 or higher and graded according to NCI 
CTCAE v5.0. 
All DLTs will be reported and the MTD and RP2D identified. 
7.2 Efficacy Endpoints 
Phase 2 
The primary efficacy endpoint of the Phase 2 portion of the study is to determine the 
ORR (rate of CR or PR) in patients with previously treated CLL/SLL according to 
IWCLL guidelines 2018 [25]. 
The secondary efficacy endpoints include:  
x 
DoR, defined as the time from documentation of tumor response to disease 
progression.  
x 
PFS, defined as the time from study enrollment until objective tumor 
progression or death. 
x 
OS, defined as the time from study enrollment to death from any cause. 
Efficacy assessments will be performed at Cycle 2/Day 28 and then every even cycle 
(Cycle 4/Day 28, Cycle 6/Day 28, etc). Response rates will be calculated in Stage 1 
and Stage 2 as per the Simon 2-stage design. 
A DSMB will monitor key outcomes from the study during the Phase 2 portion of the 
study. 


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7.2.1 
Response Criteria – 2018 IWCLL Guidelines 
Disease response will be assessed at every 2 cycles per 2018 IWCLL guidelines 
(Appendix F). 
7.3 Pharmacokinetic Endpoints 
Plasma PK analysis of oral TP-0903 will be performed in Cycle 1 on Days 1 and 28 
in all patients enrolled in the Phase 1 portion of this study. Known metabolites of 
TP-0903, if any, may also be evaluated. No PK assessments will be conducted 
during the Phase 2 portion of this study. Standard plasma PK parameters will be 
calculated, including: Cmax, Tmax, AUC from time 0 to 24 hours (AUC0-24), AUC0-inf, 
AUC from time 0 to time t (AUCt), half-life (t1/2), and clearance using 
noncompartmental methods (CL). If data permit, dose proportionality and 
accumulation ratio will be estimated in Phase 1 Cycle 1. 
Cycle 
Day 
Time Points 
1 
1 
Predose, 1 hr, 2 hrs, 6 hrs 
2 
Predose / 24 hr post Day 1 dose 
28 
Predose, 1 hr, 2 hrs, 6 hrs 
2 
1 
Predose / 24 hr post Day 28 dose 
3+ 
1 
Predose 
 
PK samples should be drawn on the protocol-specified day. 
Plasma concentrations of oral TP-0903 will be summarized by descriptive statistics, 
including mean, n, standard deviation, coefficient of variation, minimum, maximum, 
and median. A validated bioanalytical method for the detection of TP-0903 in human 
plasma has been developed prior to this study to establish assay sensitivity, 
specificity, linearity, and reproducibility. 
7.4 Pharmacodynamic Endpoints 
The PD endpoints, including biomarker assessments, will be evaluated during the 
study as follows: 
x 
Blood for potential biomarkers including, but not limited to, soluble AXL, AXL 
expression and phosphorylation, GAS6, and mesenchymal transcription 
factors   


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The above samples will be collected at timepoints described in the following table: 
Cycle 
Day 
Time Points 
1 
1 
Predose, 2 hrs, 6 hrs 
2 
Predose / 24 hr post Day 1 dose 
8 
Predose 
2+ 
1 
Predose  
End of Study 
-- 
-- 
 
Analysis of the sample will be limited to evaluations that are relative to the activity of 
the study drug or biomarkers of underlying disease. Patients may withdraw consent 
and request through the study Investigator the destruction of their sample(s) at any 
time. The samples may be retained for no longer than 20 years after study 
completion or per local requirements.  
 
 


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8. 
ADVERSE EVENTS 
8.1 Definitions 
An AE is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not 
related to the drug product. 
A suspected adverse reaction is any AE that had a reasonable possibility of being 
caused by the drug. For the purposes of Investigational New Drug (IND) safety 
reporting, reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE. 
An unexpected AE or unexpected suspected adverse reaction is an AE or suspected 
adverse reaction not listed in the current Investigator’s Brochure, not listed at the 
specificity or severity that has been observed, or not consistent with the risk 
information described in the protocol. 
Toxicities will be assessed according to the NCI CTCAE, v5.0 (Appendix D). When 
the NCI CTCAE grade is not available, the Investigator will use the following toxicity 
grading: mild, moderate, severe, life-threatening, or fatal. 
GRADE 1 – Mild: 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention 
not indicated 
GRADE 2 – Moderate: 
Minimal, local or noninvasive intervention 
indicated; limiting age-appropriate 
instrumental ADLa 
GRADE 3 – Severe: 
Medically significant but not immediately 
life-threatening; hospitalization or 
prolongation of hospitalization indicated; 
disabling; limiting self-care ADLb 
GRADE 4 – Life 
Threatening: 
Life-threatening consequences; urgent 
intervention indicated 
GRADE 5 – Fatal 
Death related to AE 
a Instrumental activities of daily living (ADLs) refer to preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc.  
b Self-care ADLs refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden. 


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8.2 Causality 
Relationship of the AE to the study drug should be defined as follows: 
Unrelated: 
AE is clearly not related to the study drug (ie, there 
is no temporal association and no other possible 
cause [intercurrent illness, medication]) 
Unlikely: 
AE is doubtfully related to the study drug 
Possibly: 
AE may be related to the study drug 
Probably: 
AE is likely related to the study drug 
Definitely: 
AE is clearly related to the study drug 
8.3 Serious Adverse Events 
An SAE is defined as any suspected adverse reaction at any dose that suggests a 
significant hazard, contraindication, side effect, or precaution, and results in the 
following outcomes: 
x 
Death; 
x 
A life-threatening event (ie, the patient is at immediate risk of death from the event 
as it occurred); 
x 
An event that is persistently, significantly, severely, or permanently disabling, or 
requires intervention to prevent such disability; 
x 
An event that requires inpatient hospitalization or prolongs hospitalization; 
x 
A congenital abnormality/birth defect; or 
x 
A medically significant event that may jeopardize the patient or may require 
intervention to prevent 1 of the other outcomes listed above. 
In addition, any AE that results in termination of the patient from the study will be 
considered a potentially serious AE and must be reported to the Sponsor as 
described in Section 8.5. 
8.4 Eliciting and Reporting Adverse Events 
All AEs, regardless of severity, that occur during the study, will be documented in 
the study progress notes, and the AE eCRF will be completed. This includes both 
serious and nonserious AEs. Adverse events occurring from the time of the first 
dose will be captured. 
All AEs noted by study staff or volunteered by study patients at any time will 
be recorded. $Q\ XQH[SHFWHG $( 1&, &7&$( *UDGH  HYHQW WKDW RFFXUV
during this study and up to 30 days after discontinuation of study drug or 
alternate cancer therapy, whichever occurs first, regardless of relationship, 
should be reported to the Medical Monitor at the next investigator or cohort 


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review call. The Principal Investigator or a qualified designated staff physician will 
conduct clinical assessments on all patients at each scheduled clinic visit. In 
addition, patients will be queried about any adverse symptoms they have 
experienced since the previous study visit. In order to avoid bias in eliciting events, 
suggestive questioning of the patients shall not occur. 
A laboratory abnormality will be reported on the AE eCRF only if it is associated with 
clinical sequelae or requires a therapeutic intervention. 
Adverse events will be reported and described in terms of intensity, seriousness, 
and causality, based on the Principal Investigator’s judgment using protocol-defined 
definitions. For both laboratory and non-laboratory abnormalities, capture only 
the highest grade of an event using start/stop dates of the longest duration. 
Necessary counter measures will also be reported on the appropriate eCRF used to 
collect concomitant medications. 
8.5 Serious 
Adverse 
Events 
and/or 
Adverse 
Events 
Requiring 
Discontinuation of Study Drug 
Any SAE that occurs during this study and up to 30 days after discontinuation of 
study drug or initiation of alternate cancer therapy, whichever occurs first, must 
be reported to the Medical Monitor within 24 hours of the Principal Investigator’s 
awareness of the event, whether or not this reaction is considered to be associated 
with the use of the investigational drug. In addition, the occurrence of any AE leading 
to permanent discontinuation of study drug must also be reported to the Sponsor 
within 24 hours of the Principal Investigator’s awareness of the event. 
All SAEs must be scanned and emailed to the Sponsor/Medical Monitor. 
Email: CRF@couranteoncology.com  
It is expected that the Principal Investigator will provide or arrange appropriate 
supportive care for the study patient. A patient experiencing an SAE should be 
followed clinically until his/her health has returned to his/her baseline status, until all 
parameters have returned to normal or have otherwise been explained, or the patient 
begins an alternative treatment regimen. All telephone and scanned/emailed reports 
must be followed with a written SAE report form within 24 hours of the Principal 
Investigator’s awareness of the SAE or nonserious event that required 
discontinuation of study drug. The SAE report form should be completed and signed 
by the Principal Investigator, scanned, and sent by email to the Sponsor as 
described above. The SAE report form is distinct and separate from the AE eCRF. 
Grades for all SAEs and AEs, regardless of whether they trigger expedited reporting, 
must be captured in the eCRF. 
8.6 Follow-Up of Adverse Events 
Any AEs that are identified on the last scheduled visit must be recorded in the AE 
eCRF page and reported to the Sponsor according to the procedures outlined in 
Section 8.4. 


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Patients with unresolved previously reported AEs or new AEs identified on the last 
scheduled visit should be followed by the Principal Investigator until the AEs resolve, 
are deemed permanent or no longer clinically significant, or the patient begins an 
alternative treatment regimen. Resolution means that the patient has returned to 
his/her baseline state of health or the Principal Investigator does not expect any 
further improvement or worsening of the AE. The Principal Investigator should 
continue to report any significant follow-up information to the Sponsor up to the time 
that the AE has resolved. Any AEs reported by the patient to the Principal 
Investigator that occur after the last scheduled visit and are determined by the 
Principal Investigator to be reasonably associated with the use of study drug or meet 
the criteria of a reportable AE as described above, should be reported to the 
Sponsor. 
Patients withdrawn from the study with an ongoing AE must be followed clinically 
until the event is resolved, deemed stable, deemed permanent, or the patient begins 
an alternative treatment regimen as determined by the Principal Investigator and 
Sponsor. A stable AE is defined as an AE that is not expected to change in nature, 
severity, or frequency. The Principal Investigator should continue to report any 
significant follow-up information to the Sponsor. 
8.7 Patient Deaths 
Every effort will be made in the case of patients who die to determine the cause of 
death. Information regarding a patient who dies more than 30 days after receiving 
study drug may be recorded on a Death Report Form (no SAE report is required). 
An SAE report is recorded only if the event leading up to the patient’s death began 
within 30 days of the last dose of study drug. 
The Death Report Form is distinct and separate from the AE eCRF. 
8.8 Reporting Adverse Events to the Regulatory Authorities 
The Sponsor will be responsible for reporting AEs to the Food and Drug 
Administration (FDA) as described in 21 CFR Section 312.32 (IND Safety Reports) 
and to other regulatory authorities according to local regulations. 
In addition, the Principal Investigator is required by FDA regulations to notify the IRB 
promptly of all unexpected SAEs occurring at the Investigator’s study site. The 
Principal Investigator is also required by FDA regulations to forward to the IRB all 
IND Safety Reports received from the Sponsor. 
The Sponsor will also report SAEs in compliance with local regulatory requirements. 


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9. 
STUDY DRUG MANAGEMENT 
9.1 TP-0903 Drug Product 
The study drug, oral TP-0903, is supplied by Tolero Pharmaceuticals as a powder in 
hard gelatin capsules (size #3 for the 1-, 4-, 16-, and 25-mg doses; size #0 for the 
100-mg dose) and is manufactured under current Good Manufacturing Practices 
(cGMP) for investigational use.  
TP-0903 capsules are formulated in 1-mg, 4-mg, 16-mg, 25-mg, and 100-mg 
strengths and are packaged into round high-density polyethylene bottles with 
polyester coils as headspace fillers. Bottles are then heat-sealed, fitted with 
child-resistant caps, and placed in low-density polyethylene bags as secondary 
packaging. 
Ibrutinib, an approved pharmaceutical product, will be provided by commercially 
available sources. 
Ibrutinib capsules for oral administration are supplied as white opaque capsules that 
contain 140 mg ibrutinib as the active ingredient. Each white opaque capsule is 
marked with “ibr 140 mg” in black ink. 
9.2 Study Drug Dispensing and Accountability 
TP-0903 will be provided by the Sponsor to study centers as an investigational drug. 
The label and package for the drug product will be prepared in accordance with 
current regulatory requirements. The Investigator or designee will inventory and 
acknowledge receipt of all shipments of study drugs. The study drugs must be kept 
in a locked area with access restricted to designated study personnel. 
An accurate and current accounting of the dispensing of the study drugs for each 
patient will be maintained on an ongoing basis by a member of the study site staff in 
a drug accountability log or equivalent document and will be verified by the Sponsor's 
study monitor. All drug supplies, including unused study drug, must be accounted 
for. A final inventory of the total amount of drug received at each study site against 
the amount used and returned must be recorded in the study drug accountability log 
or an equivalent document. Inventory and dispense records must be readily available 
for inspection by the study monitor and/or auditor, and open to government 
inspection at any time. Study drug destruction will be handled by the sites of 
open/used vials. Unopened study drug vials should be returned to the Sponsor or 
contract research organization (CRO) at the end of the study after full drug 
accountability has been completed by the study monitor.  
9.3 Storage at Study Center 
Study drug should be stored at room temperature (20°C – 25°C [68°F – 77°F] with 
excursions permitted to 15°C to 30°C [59°F to 86°F]). Protection from light is not 
necessary. 
,EUXWLQLEVKRXOGEHVWRUHGDWURRPWHPSHUDWXUHEHWZHHQ)WR)&WR& 
Please follow approved label for all instructions on storage [27].  


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9.4 Compliance 
Patients will receive both TP-0903 study drug and ibrutinib and will be followed as 
outpatients. The appropriate dose of TP-0903 to be dispensed will be determined by 
the patient’s cohort assignment. The number of study drug capsules and dosage to 
be dispensed will be recorded in an inventory log to be periodically reviewed by a 
Sponsor’s representative. 
Please refer to the Pharmacy Manual for specifics regarding dispensing of 
TP-0903 capsules. Patients will also be given a Study Drug Administration Patient 
Dosing Diary (Appendix I) in which to record the date, time, and number of capsules 
taken and also if a dose was missed or if patient vomited for both TP0903 and 
ibrutinib. Patients will be instructed to bring their Administration Diary and all study 
drug bottles to each follow-up clinic visit so that the diary can be reviewed by study 
personnel and a capsule count performed to ensure dosing compliance.  
Patients should be dispensed ibrutinib per institutional policy. 
 


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10. 
RECORD MANAGEMENT 
10.1 Data Collection 
The Principal Investigator must maintain required records for all study patients. Case 
report forms are used to record clinical study data and are an integral part of the 
study and subsequent reports. Data for this study will be recorded in the patient's 
source documents and into an eCRF system that must be kept current to reflect 
patient status during each part of the study. Patients are not to be identified by name 
on the eCRF. Appropriately coded identification (site number, patient identification 
number, and patient initials) should be used. 
The eCRFs are not to be used as source documents. The Principal Investigator must 
keep accurate separate records of all patients' visits, being sure to include all 
pertinent study-related information. A statement should be made indicating that the 
patients have been enrolled in this clinical study and have provided written informed 
consent. Any AEs must be thoroughly documented. Results of any diagnostic tests 
conducted during the study should also be included in the source documents. 
All data should be recorded completely and promptly in the eCRFs as soon after the 
visit as possible, but no later than 5 days. All queries are to be answered within 
3 days of query date. 
The Principal Investigator will allow the Sponsor, its representative, or an appropriate 
representative of the regulatory authorities to inspect study documents (eg, eCRFs, 
consent forms, study drug distribution forms, IRB/independent ethics committee 
[IEC] approval) and pertinent hospital or clinic records for confirmation of data 
throughout the study period. 
10.2 Source Document Maintenance 
Source documents, or source data, are defined as the records of original 
observations and activities of a clinical investigation. Source documents may 
include, but are not limited to, hospital medical records, study progress notes, ICFs, 
computer printouts, laboratory data, and recorded data from automated instruments. 
All source documents produced in this study will be maintained by the Principal 
Investigator and made available for inspection by representatives of the Sponsor or 
the regulatory authorities. The original signed ICF for each participating patient shall 
be filed with the records kept by the Principal Investigator, a copy filed in the patient’s 
medical records, and a copy given to the patient. 
Source documents are necessary for the reconstruction and evaluation of a clinical 
study. The purpose of source documents is to provide proof of a participant’s 
existence, confirm that protocol-related procedures were completed and conducted 
per protocol, and to verify that data reported in the study eCRFs are accurate. 
Source documents at a study site may be maintained in paper or electronic format 
and typically contain the types of information below. If electronic source documents 
are used, the Sponsor and study monitors will be given access to verify study data. 


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Source documents may include, but are not limited to: 
x 
Notes from clinic physicians, nurses, and other study staff 
x 
Reports of procedures and tests 
x 
Flow sheets, checklists, and worksheets 
x 
Patient diaries and study calendars 
x 
Pharmacy records, accountability logs, and shipping receipts 
x 
Study notes or memos to file 
x 
Documentation of telephone calls, emails, and faxes 
x 
Hospital admission forms and discharge summaries 
x 
Sponsor- or site-generated study source document templates 
Source documents must meet 5 fundamental principles of data quality (“ALCOA”). 
They must be: 
x 
Attributable – The data originator is identified. If data needs to be amended, 
the amender is identified. 
x 
Legible – The source document must be readable. If handwritten, black or 
blue ink must be used, never pencil. 
x 
Contemporaneous – The document must be signed and dated when the 
information is first recorded, with any updates or corrections noted in real 
time as well. 
x 
Original – The document must be the first place the information is recorded. 
x 
Accurate – The information must be error-free, and any conflicts with data 
recorded elsewhere must be reconciled. 
10.3 Record Maintenance 
The Principal Investigator must retain a comprehensive and centralized filing system 
of all clinical study-related documentation that is suitable for inspection by the 
Sponsor and representatives of regulatory authorities. 
The Principal Investigator must retain essential study documents (as specified in 
Section 8 of International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) and as required by the applicable regulatory requirements) until at least 
2 years after the last approval of a marketing application. Patient files and other 
source documents (including copies of protocols, eCRFs, original reports of test 
results, study drug dispensing logs, correspondence, ICFs, and other documents 
pertaining to the conduct of the study) must be kept for the maximum period of time 
permitted by the institution. 


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No study document will be destroyed without prior written agreement between the 
Sponsor and the Principal Investigator. Should the Principal Investigator wish to 
assign the study records to another party or move them to another location, written 
agreement must be obtained from the Sponsor. 
The Principal Investigator shall take responsibility for maintaining adequate and 
accurate hard-copy source documents of all observations and data generated during 
this study, including any data clarification forms received from the Sponsor. Such 
documentation is subject to inspection by the Sponsor and the FDA or other 
regulatory authorities. 
10.4 Study Center File Management 
It will be the responsibility of the Principal Investigator to assure that the study file at 
the study site is maintained. The study file for this protocol will contain, but will not 
be limited to, the information listed below: 
x 
Investigator’s Brochure, current version and all versions provided during the 
study period 
x 
Final study protocol 
x 
Protocol amendments (if applicable) 
x 
Original ICF (blank) 
x 
Revised ICFs and/or all addenda (if applicable) 
x 
Copy of signed FDA Form(s) 1572 
x 
Curricula vitae and medical licenses of Principal Investigator and 
Subinvestigators 
x 
Financial disclosure form of Principal Investigator and Subinvestigators (if 
applicable) 
x 
Department of Health and Human Services number for IRB, or other 
documentation of IRB compliance with FDA regulation (United States sites) 
x 
Documentation of IRB/IEC approval of protocol, ICF, any protocol 
amendments, and any ICF revisions 
x 
Annual IRB/IEC updates and approvals 
x 
All correspondence between the Principal Investigator, IRB/IEC, and 
Sponsor or Sponsor’s representative relating to study conduct 
x 
Copies of all 7-day and 15-day Safety Reports submitted to the regulatory 
authorities (provided by Sponsor) and IRB/IEC correspondence documenting 
their submission 
x 
Laboratory certifications 
x 
Normal laboratory value ranges for tests required by the protocol for all 
laboratories that are utilized 
x 
Clinical research associate (CRA) monitoring log 
x 
List of signatures and delegation of authority for all study personnel 
x 
Invoices for both receipt and return of study drug and drug 
inventory/accountability records 
 


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11. 
STATISTICAL ANALYSIS 
This is a Phase 1/2, multi-center, single-agent, open-label study in which Phase 1 
will employ the 3+3 dose escalation design and Phase 2 uses the Simon 2-stage 
design. 
Results of statistical analyses, descriptive statistics, and supporting listings will be 
presented by study phase (Phase 1 and Phase 2) and patient group (TP-903 
monotherapy and combination therapy with ibrutinib).  
Statistical analysis for all safety and efficacy parameters will be primarily descriptive 
in nature. Categorical variables will be summarized by frequency distributions 
(number and percentages of patients), continuous variables will be summarized by 
mean, standard deviation, median, minimum, maximum, and time-to-event variables 
will be summarized using Kaplan-Meier methods and figures for the estimated 
median time. No formal statistical hypothesis testing is planned; however, if 
exploratory analyses are conducted and confidence intervals are provided for 
estimates, the 95% confidence intervals are consistent with a 2-sided 5% 
significance level. All analyses, summaries, and listings will be performed using 
Statistical Analysis System (SAS) software (version 9.4 or higher). 
A detailed methodology for summary and statistical analysis of the data collected in 
this study will be documented in a Statistical Analysis Plan (SAP) that will be finalized 
prior to database lock. If any modifications to the analyses outlined in the protocol 
are made, these will be clearly documented in the SAP. Any major modifications of 
the study design or study endpoints and/or its analysis will also be reflected in a 
protocol amendment. 
11.1 Sample Size 
Phase 1 
Patients will be enrolled for each patient group (TP-0903 monotherapy and 
combination therapy with ibrutinib) in cohorts of 3 to 6 patients. Escalation of the 
TP-0903 dose will follow a standard 3+3 design with sequential cohorts of 3 patients 
treated with incrementally higher doses of TP-0903 until a DLT is observed and the 
MTD is established. Based on the standard oncology 3+3 Phase 1 dose escalation 
design, the total number of patients to be enrolled cannot be precisely determined 
as the sample size is dependent upon the observed safety profile, which will 
determine the number of patients per dose cohort, as well as the number of dose 
escalations required to achieve the MTD. It is anticipated that 12 to 21 patients will 
be required to achieve MTD dose level. Once the MTD or preliminary RP2D is 
identified, an expansion cohort of approximately six patients will be enrolled to 
confirm safety/suitability of the preliminary RP2D, to collect additional biomarker 
data, and to further explore efficacy. It is expected that up to 27 patients will be 
enrolled in each patient group (monotherapy and combination therapy). 
7KH07'LVGHILQHGDVWKHGRVHDWZKLFKRISDWLHQWVH[SHULHQFHD'/7GXULQJ
Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a 
DLT during Cycle 1. Once the MTD or preliminary RP2D is identified, the study will 
progress to Phase 2. 


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Phase 2 
The statistical power calculations for each patient group (monotherapy and 
combination therapy) are based on the Simon 2-stage minimax design [27]. 
x 
Stage 1: Up to 13 evaluable patients will be enrolled and treated at the RP2D 
identified in the Phase 1 part of this study. Stage 2 may be initiated at any 
point after confirming a response (CR or PR) in at least one Stage 1 patient. 
If there are zero responders among 13 evaluable Stage 1 patients, the study 
will be stopped after Stage 1. 
x 
Stage 2: Fourteen patients will be enrolled to bring the total enrollment in 
Phase 2 (including Stage 1 patients) to 27 evaluable patients. Stage 2 
patients will also receive the RP2D dose identified in the Phase 1 study. If 4 
or more responses are observed in 27 patients, the conclusion will be that 
the combination regimen is worthy of further investigation. When the true 
response rate of 20% (alternative hypothesis) is tested against the null 
hypothesis response rate of 5%; this design yields a Type I error rate of 0.05 
and power of 80%. 
If both patient groups (Group 1 and Group 2) enroll through Stage 2, it is anticipated 
that the total enrollment for Phase 2 will be 54 patients (n=27 for Group 1 [ie, 
TP-0903 monotherapy] and n=27 for Group 2 [ie, combination therapy]) (Table 5). 
Table 5 Sample Size Description 
Patient Group 
Phase 1 
Phase 2 
Dose 
Escalation 
Dose 
Expansion 
Simon Stage 
1 
Simon Stage 
2 
Monotherapy 
12 - 21 
6 
13 
+14 = 27 
Combination 
Therapy 
12 - 21 
6 
13 
+14 = 27 
Total 
24 - 42 
12 
26 
+28 = 54 
 
Any patient who withdraws from Stage 1 or 2 for treatment-related toxicity or disease 
progression or dies prior to being evaluated for response, will be considered a 
nonresponder. Patients who drop out for other reasons prior to being assessed for 
response will be considered unevaluable and may be replaced.  
Enrollment into Phase 2 can open in a specific group (monotherapy or combination 
therapy) once MTD has been reached in that group.  Enrollment into Phase 2 may 
EHVWRSSHGDWDQ\SRLQWRQFHSDWLHQWVKave had a response to treatment, but the 
maximum enrollment in Phase 2 will be 27 evaluable patients per patient group. 


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11.2 Analysis Population Sets 
This study will have 3 analysis populations: 
x 
Intent-to-Treat (ITT) Analysis Set includes all patients who are enrolled in the 
study. 
x 
Safety Analysis Set consists of all patients who receive study drug (TP-0903). 
x 
Response Evaluable Set consists of patients who have at least one 
postbaseline efficacy assessment; patients without a postbaseline efficacy 
assessment will not be considered evaluable for the primary efficacy 
analysis. Patients who discontinue due to disease progression or die of 
treatment-related toxicity prior to having a disease assessment will be 
included in the Response Evaluable population. 
11.3 Data Analyses 
11.3.1 
Patient Disposition 
A detailed description of patient disposition will be provided and will include the 
following: 
x 
The number of patients who are enrolled, included in the ITT, Safety, and 
Response Evaluable analysis sets. 
x 
A summary of patient dose cohorts. 
x 
A summary of patients who complete the protocol. 
x 
A summary of reasons for withdrawal from study. 
x 
A summary of reasons for patients with treatment failure. 
x 
An account of all identified protocol violations. 
x 
All patients enrolled in the study will be accounted for in the summation. 
11.3.2 
Demographic and Baseline Characteristics 
Demographic characteristics including age, gender, race, and ethnicity will be 
presented in the form of tabulated summary statistics. Other patient baseline 
characteristics including but not limited to: weight, height, body mass index (BMI), 
initial stage of disease, prior therapies, and ECOG performance status will be 
presented similarly. 
11.3.3 
Concomitant Medications 
The number and proportion of patients using different concomitant medications will 
be tabulated and summarized by World Health Organization (WHO) Drug anatomical 
therapeutic chemical (ATC) and preferred term. 


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11.3.4 
Treatment Administration/Compliance 
Study drug administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered, dose intensity, and 
reasons for the deviations from planned therapy. 
11.3.5 
Efficacy Analysis 
The primary efficacy endpoint is ORR, defined as the percent of patients with CR or 
PR according to IWCLL guidelines 2018, relative to the Response Evaluable 
population. 
The secondary efficacy endpoints are as follows: 
x 
DoR, defined as the time from documentation of tumor response to disease 
progression.  
x 
PFS, defined as the time from first dose until objective tumor progression or 
death. 
x 
OS, defined as the time from first dose to death from any cause. 
ORR will be summarized by number and percentage of patients meeting the 
definition of ORR along with the corresponding exact 95% confidence intervals. 
Time-to event endpoints (DoR, PFS, and OS) will be summarized by Kaplan-Meier 
methods (median, 95% CI, number of events, number censored, and Kaplan-Meier 
figures). 
Additional analyses may be performed to assist the Sponsor in planning future 
studies.  
11.3.6 
Safety Analysis 
Safety will be monitored during the period starting on the date of first dose and 
ending 30 days after the final administration of TP-0903. During Phase 1, the safety 
endpoints will be evaluated after Cycle 1. The dose escalation committee will have 
access to complete safety profiles of all patients receiving TP-0903 and will be able 
to take decisions accordingly. 
All patients who receive any dose (any amount) of TP-0903 will be included in the 
summaries and listings of safety data. Overall safety profile will be characterized by 
type, frequency, seriousness, severity, timing, duration and relationship of study 
drug of AEs and laboratory abnormalities. 
11.3.6.1 Adverse Events 
AEs will be classified using the MedDRA classification system v20.0 or higher. The 
severity of the toxicities will be graded according to the NCI CTCAE v5.0. 
In all summaries, emphasis will be placed on TEAEs, namely, those with initial onset 
or that worsen in severity after the first dose of TP-0903. AEs will be summarized by 
the frequency of patients experiencing TEAEs corresponding to body systems and 


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MedDRA preferred term and by worst NCI CTCAE v5.0 grade. Summaries will also 
be provided of treatment related TEAEs, namely, those judged by the investigator to 
be related or possibly related to TP-0903 and/or combination therapy. 
AEs resulting in discontinuation of TP-0903 treatment or withdrawal from the study, 
Grade 3 or higher, SAEs, and deaths on-study will be tabulated. All DLTs will be 
reported and the MTD and RP2D identified. 
All DLTs will be reported and the MTD and RP2D identified. 
11.3.6.2 Laboratory Parameters 
Laboratory data will be summarized for the observed values at each scheduled 
assessment, together with the corresponding changes from baseline (the value 
obtained prior to dosing on Cycle 1/Day 1) using descriptive statistics.  
For those analytes with CTCAE grades, abnormal laboratory values will be 
summarized by dose group and overall by shift tables displaying numerical values 
and percentages classified by Baseline grade (ie, grade prior to dosing on 
Cycle 1/Day 1) and maximum grade on treatment. All laboratory data will be 
presented in listings. 
11.3.6.3 Electrocardiogram 
The ECG parameters (PR interval, QRS duration, QT, QTc, and QTcF) will be 
summarized descriptively by dose cohort and overall for each time point for both the 
observed values and the change from Baseline to each postbaseline time point. The 
number and percentage of patients with QT or QTc (QTcF) outlier values (at any 
postbaseline time point), as defined in ICH E14, will be summarized. 
11.3.6.4 Vital Signs and Physical Examination 
Vital signs data will be summarized by the observed value at each scheduled 
assessment, together with the corresponding changes from Baseline using 
descriptive statistics. 
Physical examination findings will be presented in data listings. 
11.3.7 
Pharmacokinetic Analysis 
PK parameters will be estimated using standard noncompartmental methods and 
according to FDA guidance [26]. 
The PK parameters will include: 
x 
Cmax = maximum observed plasma concentration 
x 
Tmax = time to Cmax (peak time) 
x 
AUC0-24 = area under the plasma concentration curve from time 0 to 24 hours 
x 
AUC0-inf = AUC from time 0 to infinity 
x 
AUCt = area under the plasma concentration curve from time 0 to time t 
x 
t1/2 = half-life 
x 
CL = clearance using noncompartmental methods 


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Actual sample collection times will be used rather than scheduled collection times. 
Plasma concentrations below the limit of quantification will be treated as “0”. 
Imbedded missing plasma concentrations (ie, missing values between 2 observed 
values) will be estimated using linear extrapolation. This is consistent with using the 
trapezoidal rule to calculate AUC. Other missing plasma concentrations will be 
excluded from calculations to estimate PK parameters. 
11.3.8 
Pharmacodynamic Analysis 
The PD relationships of TP-0903 exposure with exploratory biomarkers will be 
quantified using the Spearman rank correlation statistic to examine the relationships 
between response to treatment (ordered categorical dependent variables) and 
changes from baseline values of PD endpoints (continuous independent variables). 
11.4 
Interim Analysis 
Phase 1 
Safety data will be monitored continuously per standard Phase 1 oncology study 
practices. 
Phase 2 
Since the Simon 2-stage design will be employed, response rate data will be 
assessed after Stage 1 and Stage 2. 
 
 


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12. 
PROTOCOL AMENDMENTS 
Any permanent change to the protocol must be handled as a protocol amendment. 
Protocol amendments will be written by the Sponsor. All protocol amendments must 
be submitted in writing to the IRB/IEC, and the Principal Investigator must await 
IRB/IEC approval of the amendments before implementing the changes. However, 
a protocol change which is intended to eliminate an apparent immediate hazard to 
patients may be implemented immediately, provided that the IRB/IEC is notified 
within 5 days. The Sponsor should also be notified by telephone as soon as possible, 
ideally before the amendment is implemented and definitely within 5 days. The 
Sponsor will submit protocol amendments to the regulatory authorities. 
When an amendment to the protocol substantially alters the study design and/or 
increases the potential risk to the patient, the currently approved written ICF will 
require similar modification and IRB/IEC approval. In such cases, repeat written 
informed consent will be obtained from patients currently enrolled in the study before 
expecting continued participation. 
 
 


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13. 
MONITORING 
Before enrolling any participants, a study initiation visit, including protocol training, 
will be conducted for the study site. A Study Manual of Procedures will be provided 
to each study site. A record of study site personnel training will be maintained on the 
study site onsite training logs. 
Clinical research associates and other applicable personnel will receive training 
before study initiation about the disease, applicable Standard Operating Procedures 
(SOPs), the protocol, and other study-specific items. Team organization, 
communication, and operational issues will also be discussed. 
The conduct of the study will be closely monitored by representatives (CRAs) of the 
Sponsor or designee, to verify adherence to the protocol, ICH GCP guidelines, and 
applicable regulations. The CRA will verify eCRF entries by comparing them with 
Sponsor- or site-generated source documents and hospital, clinic, office, and/or 
study records which will be made available for this purpose. The CRAs will monitor 
the study as outlined in the Monitoring Plan prepared for the study. 
During the study, CRAs will visit the study sites to assess and assure satisfactory 
enrollment rate, data recording, maintenance of required regulatory and drug 
accountability documentation, and compliance with the protocol. The CRAs will also 
be able to monitor the data remotely. The Principal Investigator will ensure that all 
requested materials, including patient medical records, eCRFs, source documents, 
laboratory records, and drug inventory records, will be available to the CRA. At the 
end of the study, a closeout visit will be performed. 
The Principal Investigator will allow the Sponsor, its representatives, and/or any 
regulatory agency to have direct access to all study records, eCRFs, patient medical 
records, study drug dispensing records, the study drug storage area, and any other 
documents considered source documentation. The Principal Investigator also 
agrees to assist the representative, if required. 
 
 


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14. 
AUDITING 
The study is conducted under the sponsorship of Tolero, in compliance with the 
applicable international and local regulatory requirements and applicable ICH 
guidelines, Declarations of Helsinki (1964, 1975, 1983, 1989, 1996, 2000, 2002, 
2004, 2008, 2013) and in respect of the Sponsor or designee’s SOPs for study 
conduct and monitoring. 
Audits or inspections may be carried out by the Sponsor, its representatives, 
regulatory authorities, or IRBs/IECs before, during, or after the study. For audits 
performed by, or on behalf of, the Sponsor, audit findings will be provided by quality 
assurance, in writing. 
 
 


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15. 
ETHICS AND RESPONSIBILITY 
15.1 Principal Investigator’s Responsibilities 
The Principal Investigator shall ensure that all work and services described herein, 
or incidental to those described herein, shall be conducted in accordance with the 
highest standards of GCP. The Principal Investigator shall administer the study drug 
only to patients under his/her personal supervision, or under the supervision of any 
Subinvestigator responsible to him/her, who are identified on the Form FDA 
1572/Statement of Investigator. The Principal Investigator will provide copies of the 
study protocol, amendments, and Investigator’s Brochure to all Subinvestigators, 
pharmacists, or other staff responsible for study conduct. 
With the exception of eliminating an immediate hazard to a patient (refer to 
Section 12), the Investigator should not deviate from the protocol or implement any 
changes unless a protocol amendment has been written by the Sponsor and 
approved by the IRB/IEC. 
Changes which involve only logistical or administrative matters are authorized. The 
Investigator should document and explain any deviation from the protocol. 
The Investigator is responsible for adequate and safe medical care of patients during 
the study and for ensuring that appropriate medical care and relevant follow-up 
procedures are maintained after the study. Any additional data from these follow-up 
procedures must be documented and available to Sponsor who will determine 
whether or not the data need to be documented in the eCRFs. 
15.2 Informed Consent 
It is the ethical and legal responsibility of the Principal Investigator to ensure that 
each patient considered for inclusion in this study is given a full explanation of the 
protocol, in a language in which the patient is fluent, and in which the patient will 
clearly understand. This shall be documented on a written ICF, which shall be 
approved by the same IRB/IEC responsible for approval of this protocol. Each ICF 
shall include the elements required by local regulations. The Sponsor will draft this 
document in consultation with the Principal Investigator. The Principal Investigator 
agrees to obtain written approval of the ICF from the Sponsor before submission to 
the IRB/IEC. 
Once the appropriate essential information has been provided to the patient and fully 
explained by the Principal Investigator (or his/her qualified designee) and it is felt 
that the patient understands the implications of participating in the study, the 
IRB/IEC-approved ICF shall be signed by the patient, a witness (when appropriate), 
and the Principal Investigator (or designee). Written informed consent will be 
obtained from each patient before any study-related procedures (including any 
pretreatment procedures) are performed. The patient shall be given a copy of the 
ICF once signed. The original shall be kept on file by the Principal Investigator and 
a second copy shall be placed in the patient’s medical chart (or per electronic 
medical record SOP). 


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15.3 Institutional Review Board 
This protocol and all amendments will be reviewed and approved by the IRB/IEC 
charged with this responsibility by the study site. Notification in writing of approval 
must come from the chairman or the secretary of the IRB/IEC and recorded in the 
meeting minutes where this protocol and associated ICF were discussed. The 
Principal Investigator shall not participate in the decision, and if he/she is an IRB/IEC 
member, the written approval must indicate such nonparticipation. The Principal 
Investigator shall submit status reports to the IRB/IEC no less frequently than 
annually (when applicable). The IRB/IEC must be notified by the Principal 
Investigator in writing of the interruption and/or completion of the study. The Principal 
Investigator must promptly report to the IRB/IEC all changes in the study (protocol 
amendments) and will not make such changes without IRB/IEC approval, except 
where necessary to eliminate apparent immediate hazards to patients. In these 
cases, the IRB/IEC must be notified within 5 days of the change. The Principal 
Investigator will promptly report to the IRB/IEC all unanticipated problems involving 
risk to patients or others. The Principal Investigator is required to maintain an 
accurate and complete record of all written correspondence to and from the IRB/IEC 
and must agree to share all such documents and reports with the Sponsor. 
 
 


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16. 
CONFIDENTIALITY 
The details of this clinical study are confidential (with exception of listing on 
clinicaltrials.gov) and should not be discussed with persons outside of the study. The 
Investigator shall hold confidential, and not disclose directly or indirectly to any third 
party other than those persons involved in the study who have a need to know, the 
protocol, the data arising out of the study, or any other information related to the 
study or to Tolero’s products or research programs that are provided by Tolero. All 
such persons must be instructed not to further disseminate this information to others. 
The Investigator shall not use the confidential information for any purpose other than 
study conduct. The foregoing obligations of confidence and nonuse assumed by the 
Investigator shall not apply to: (a) information that at the time of disclosure is in the 
public domain; (b) information that thereafter lawfully becomes part of the public 
domain other than through disclosure by or through you; (c) information that, as 
evidenced by the Investigator’s written records, was known by the Investigator 
before Tolero’s disclosure; (d) information that is lawfully disclosed to you by a third 
party not under any obligation of confidence to Tolero; or (e) information that is 
required to be disclosed by law or governmental regulatory agency, provided 
reasonable advance notice of such disclosure is given to Tolero. 
All information generated in this study must be considered highly confidential and 
must not be disclosed to any persons not directly concerned with the study, without 
written permission from the Sponsor. However, the Sponsor, its representatives, 
regulatory authorities, and IRBs/IECs will be allowed full access to the records. 
Patients will be identified only by initials and assigned patient number in eCRFs. 
Their full names may, however, be made known to a regulatory authority or other 
authorized official if necessary. 
All data and discoveries arising out of the study, patentable or nonpatentable, shall 
be the sole property of Tolero. 
In signing this protocol, the Principal Investigator agrees to the release of the data 
from this study and acknowledges the above confidentiality and publication policy. 
The provisions of this statement shall survive the completion of the study. 
Clinical information will not be released without the written permission of the patient, 
except as necessary for monitoring by the Sponsor or regulatory authorities, or as 
required by law. 
 
 


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17. 
NONPROTOCOL RELATED RESEARCH 
The Sponsor has a legal responsibility to report fully to regulatory authorities all the 
results of administration of investigational drugs. No investigative procedures other 
than those in this protocol shall be undertaken on the enrolled patients without the 
agreement of the IRB/IEC and the Sponsor’s Medical Monitor. 
 
 


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18. PUBLICATIONS 
The publication policy for the study will be described in the clinical study agreement. 
To avoid disclosures that could jeopardize proprietary rights, the Investigator agrees 
to give Tolero the right to review all manuscripts, abstracts, and presentations related 
to this study prior to their submission for publication or presentation. Tolero may use 
these data now and in the future for presentation or publication at Tolero’s discretion 
or for submission to government regulatory agencies.  
Authorship among Investigators generally will be based on the extent of significant 
contribution, including scientific and clinical, to the publication. 


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19. 
REFERENCES 
1. Verma A, Warner SL, Vankayalapati H, Bearss DJ, and Sharma S. Targeting 
AXL and MER kinases in cancer. Mol Cancer Ther 2011;10:1763–1773. 
2. Jacob AN, Kalapurakal J, Davidson WR, Kandpal G, Dunson N, Prashar Y, 
et al. A receptor tyrosine kinase, UFO/AXL, and other genes isolated by a 
modified differential display PCR are overexpressed in metastatic prostatic 
carcinoma cell line DU145. Cancer Detect Prev 1999;23:325–32. 
3. Stitt TN, Conn G, Gore M, Lai C, Bruno J, Radziejewski C, et al. The 
anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 
3/AXL family of receptor tyrosine kinases. Cell 1995;80:661–670. 
4. Mudduluru G, Vajkoczy P, Allgayer H. Myeloid zinc finger 1 induces 
migration, invasion, and in vivo metastasis through AXL gene expression in 
solid cancer. Mol Cancer Res MCR 2010;8:159–169. 
5. Nakano T, Tani M, Ishibashi Y, Kimura K, Park YB, Imaizumi N, et al. 
Biological properties and gene expression associated with metastatic 
potential of human osteosarcoma. Clin Exp Metastasis 2003;20:665–674. 
6. Sinha S, Boysen J, Nelson M, Secreto C, Warner SL, Bearss DJ, et al. 
Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B-Cells to 
Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK 
Inhibitors. Clin Cancer Res 2015;21(9):2115–2216. 
7. Sinha S, Boysen J, Nelson M, Warner SL, Bearss D, Kay NE, et al. Axl 
activates fibroblast growth factor receptor pathway to potentiate survival 
signals 
in 
B-cell 
chronic 
lymphocytic 
leukemia 
cells. 
Leukemia 
2016;30(6):1431–1436. 
8. Ghosh AK, Secreto CR, Knox TR, Ding W, Mukhopadhyay D, Kay NE. 
Circulating microvesicles in B-cell chronic lymphocytic leukemia can 
stimulate marrow stromal cells: implications for disease progression. Blood 
2010;115(9):1755–1764. 
9. Boysen J, Sinha S, Price-Troska T, Warner SL, Bearss DJ, Viswanatha D, et 
al. The tumor suppressor axis p53/miR-34a regulates Axl expression in B-cell 
chronic lymphocytic leukemia: implications for therapy in p53-defective CLL 
patients. Leukemia 2014;28(2):451–455. 
10. Study No. 20120617: hERG profiling report. Reaction Biology Corp. Malvern, 
PA.  
11. Study No. 100020442: In vitro pharmacology and ADME-tox study of 
TP-3654 and TP-0903. Final Report. CEREP, Inc. Redmond, WA. 
12 February 2015. 


Protocol No. TP-0903-102 Amendment 2 
 
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12. Study No. 302456: A 28-day repeated oral dose toxicity study of TP-0903 in 
Beagle dogs followed by a 14-day recovery period. Draft Study Report #1. 
NucroTechnics, Ontario, Canada. 11 December 2015. 
13. Study No. 302457: A 28-day repeated oral dose toxicity study of TP-0903 in 
Sprague-Dawley rats followed by a 14-day recovery period. Draft Study 
Report #1. NucroTechnics, Ontario, Canada. 18 December 2015. 
14. Study No. 302504: A telemetry cardiopulmonary safety study following oral 
dosing of TP-0903 in conscious female beagle dogs. Draft Report. 
NucroTechnics, Ontario, Canada. 08 January 2015. 
15. Rescigno J, Mansukhani A, Basilico C. A putative receptor tyrosine kinase 
with unique structural topology. Oncogene 1991;6:1909–1913. 
16. Vajkoczy P, Knyazev P, Kunkel A, Capelle HH, Behrndt S, von Tengg-
Kobligk H, et al. Dominant-negative inhibition of the AXL receptor tyrosine 
kinase suppresses brain tumor cell growth and invasion and prolongs 
survival. Proc Natl Acad Sci USA 2006;103:5799–804. 
17. Ekman C, Stenhoff J, Dahlbäck B. GAS6 is complexed to the soluble tyrosine 
kinase receptor AXL in human blood. J Thromb Haemost JTH 2010;8:838–
844. 
18. Ghosh AK, Secreto CR, Boysen J, Sassoon T, Shanafelt TD, Mukhopadhyay 
D, et al. The novel receptor tyrosine kinase Axl is constitutively active in B-cell 
chronic lymphocytic leukemia and acts as a docking site of nonreceptor 
kinases: implications for therapy. Blood 2011;117:1928–1937. 
19. Patel V, Keating MJ, Wierda WG, Gandhi V. Preclinical combination of 
TP-0903, an AXL inhibitor and B-PAC-1, a procaspase-activating compound 
with 
ibrutinib 
in 
chronic 
lymphocytic 
leukemia. 
Leuk 
Lymphoma 
2016;57(6):1494–1497. 
20. Study No. 191081: Effects of HCI-2084, HCI-2151 and HCI-2153 on the 
cloned hERG potassium channels. Final Report. GenScript, Piscataway, NJ.  
21. Study No. 20130208-1: Valuation of the effects of TP-0903 and TP-0904 on 
the human potassium channel using human embryonic kidney (HEK) 293 
cells transfected with a human ether-a-go-go-related gene (hERG). Final 
Report. IPS Therapeutique Inc (IPST), Sherbrooke, QC, Canada. 
20 February 2013. 
22. Study No. 293892: A 7-day repeated oral dose range-finding study of 
TP-0903 with single and repeated dose PK in rats. Final Study Report. 
NucroTechnics, Ontario, Canada. 03 June 2015. 
23. Study No. 294865: A single, oral, dose range-finding study followed by a 
7-day, repeated-dose toxicity and pharmacokinetic study of TP-0903 in 
Beagle dogs. Draft Study Report #2. NucroTechnics, Ontario, Canada. 16 
June 2015. 


Protocol No. TP-0903-102 Amendment 2 
 
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24. Study No. 298717: A 7-day, three times a day, repeated dose toxicity, 
recovery and pharmacokinetic study of TP-0903 in Beagle dogs. Draft Study 
Report #1. NucroTechnics, Ontario, Canada. 17 September 2015. 
25. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner 
H, et al. Guidelines for Diagnosis, Indications for Treatment, Response 
Assessment and Supportive Management of Chronic Lymphocytic Leukemia 
(An Update of the NCI-sponsored guidelines from the International Workshop 
on Chronic Lymphocytic Leukemia). Prepublished online March 14, 2018; 
doi:10.1182/blood-2017-09-806398. 
Available 
from: 
http://www.bloodjournal.org/content/early/2018/03/14/blood-2017-09-
806398  
26. Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (US). Draft guidance. Guidance for 
Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs or 
INDs — General Considerations. March 2014 [cited 07 March 2018]. 
Available 
at: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinform
ation/guidances/ucm389370.pdf. 
27. Full Prescribing Information for IMBRUVICA® (ibrutinib) capsules, for 
oral use. Pharmacyclics LLC, Sunnyvale, CA, USA 94085. Revised 
August 
2018. 
Available 
at:  
https://www.imbruvica.com/docs/librariesprovider7/default-document-
library/prescribing-information.pdf. Accessed on: 16 October 2018. 
28. Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials; Controlled 
Clinical Trials 1989;10(1):1–10.


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APPENDIX A – SCHEDULE OF ASSESSMENTS 
CYCLE DAY 
SCREENING 
(Day -14 
to Day 1) 
CYCLE 1 
CYCLE 2 
CYCLE  
End-of-
Study 
Visita 
30-day 
(+14) 
Follow-
Upb 
LTFUw 
Year 1 
(± 7 days) 
(Monthly) 
LTFUw 
Year 2 
(±14 days) 
(Every other 
Month) 
–72 hr 
to  
Day 1 
1 
8 
(±3) 
15 
(±3) 
22 
(±3) 
28 
(±3) 
1 
(±2) 
15 
(±3) 
28 
(-4) 
1 
(±2) 
15 
(±3) 
28 
(-4) 
PROCEDURE/ASSESSMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X m,n 
X 
X 
 
 
 
 
X 
 
 
X 
 
Xm,n 
X 
 
 
 
Abbreviated physical 
examinationd 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Baseline signs/symptoms 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
ECOG performance status 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Serum chemistryf 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
CBC with differential and 
platelet counts 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Coagulation parameters 
(PT and aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS labsy 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Confirm eligibilityi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG including 
assessment of QTcFj 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Concomitant medicationsk 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Assess AEsl 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Disease assessmentm 
X 
 
 
 
 
 
 
 
 
X 
 
 
Xn 
Xo 
 
 
 
Bone marrow 
X 
 
 
 
 
 
 
 
 
 Xv 
 
 
Xv 
Xv 
 
 
 
CT scanp 
X 
 
 
 
 
 
 
 
 
X 
 
 
Xn 
Xo 
 
 
 
PET scan 
 Xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for disease 
assessment 
X 
 
 
 
 
 
 
 
 
Xq 
 
 
Xq 
Xq 
 
 
 
Blood for biomarkersr 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
Xo 
 
 
 
PK blood sampless 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Study drug administrationt 
 
 
Daily 
Daily 
Daily 
 
 
 
 
Dosing diaryu 
 
 
Daily 
Daily 
Daily 
 
 
 
 
Telephone contact 
 
 
 
 
 
 
 
X 
X 


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AE: adverse event; aPTT: activated partial thromboplastin time; ȕ-hCG: beta human chorionic gonadotropin; CBC: complete blood count; 
CLL: chronic lymphocytic leukemia; CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; 
IWCLL: International Workshop on Chronic Lymphocytic Leukemia; MRD: minimal residual disease; PK: pharmacokinetic; PT: prothrombin time; 
QTcF: corrected QT interval (using Fridericia’s correction formula); SLL: small lymphocytic lymphoma; TLS: tumor lysis syndrome 
Notes: 
a 
If, at any time, a patient discontinues study treatment, a visit should be scheduled as soon as possible and within 14 days of the last dose of 
study drug or within 14 days of the decision to discontinue study treatment. If the decision to withdraw the patient occurs at a regularly scheduled 
visit, that visit may become the End-of-Study Visit rather than having the patient return for an additional visit. 
b 
Patients must undergo a safety evaluation in which the condition of the patient during 30 days after the last dose of study drug can be 
assessed. There is a visit window of up to 14 days after completion of the 30 days from the last dose (ie, within 45 days after last dose 
of study drug). 
c 
Complete medical history including histologically confirmed diagnosis of CLL/SLL  
d 
Abbreviated physical examination (AE- or symptom-directed). 
e 
Vital signs to include: body temperature, respirations, heart rate, blood pressure. 
f 
Full serum chemistry panel to include: blood urea nitrogen, phosphorus, magnesium, lactate dehydrogenase, creatinine, uric acid, total protein, 
albumin, calcium, glucose, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase. Collection of blood for 
analysis of serum electrolytes, immunoglobulin, and direct antiglobulin will be conducted at screening only (Appendix E). 
g 
Urinalysis to include: color, specific gravity, pH, bilirubin, ketones, glucose, occult blood (hemoglobin), leukocyte esterase, protein, urobilinogen, 
nitrites, white blood cells, red blood cells, casts, crystals, bacteria (Appendix E). 
h 
Urine or serum sample for beta-human chorionic gonadotropin pregnancy test from females of childbearing potential. 
i 
Review all inclusion and exclusion criteria to determine if patient has met all eligibility criteria for enrollment into the study. Obtain Medical Monitor 
(or designee) approval to enroll patient. 
j 
12-lead ECG will be performed on Day 1 of each cycle prior to dosing (predose). 
k 
Including all prescription drugs, nonprescription drugs, and nutritional supplements. 
l 
AEs will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
(Appendix D). When the NCI CTCAE grade is not available, the Investigator will use the following severity grading: mild, moderate, severe, 
life-threatening, or fatal. 
m Disease assessment per 2018 IWCLL guidelines 2018 (Appendix F), including review of constitutional symptoms to include unintentional weight 
loss, fatigue, fevers, and night sweats will be completed at Screening, Cycle 2/Day 28, and then every other cycle on Day 28 (Cycle 4, Cycle 6, 
etc). 
n 
Day 28 of every EVEN cycle (ie, Cycle 4, Cycle 6, etc). 
o 
,I  ZHHNV VLQFH ODVW UHVSRQVH DVVHVVPHQW GLVHDVH VWDWXV ZLOO EH DVVHVVHG DV SHU ,:&// JXLGHOLQHV 18 (Appendix F). If patient has 
unequivocal evidence of disease progression, then this reassessment may be eliminated. 
p 
CT scan of neck, chest, abdomen, and pelvis evaluation of lymphadenopathy, hepatomegaly, and splenomegaly. 
q 
Collect blood only at CR for determination of MRD (central lab assessment) 
r 
Collect blood for PD PBMCs, plasma and serum at C1D1 pre-dose, 2 hr, 6 hr and 24 hr postdose (predose C1D2), C1D8 predose and Day 1 of 
every cycle and EOS 
s 
PK samples will be collected only in the Phase 1 portion of the study, on Days 1 and 28 of Cycle 1 just before dosing and at 1, 2, 6, and 24 hours 
postdose (prior to the next daily dose of TP-0903) and on Day 1 of each subsequent cycle. PK samples should be collected on protocol-
specified days, regardless of visit windows. 


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t 
Study drug should be taken in the morning after an overnight fast with up to 200 mL or 7 fluid ounces of water at least 1 hour before ingesting 
any food or other medications. For patients in Group 2, ibrutinib should be taken as directed and per the approved label instructions. 
u 
Patients will be given a Patient Dosing Diary (Appendix I) in which to record the date, time, number of capsules taken, whether a dose was 
missed, or if patient vomited for both TP-0903 and ibrutinib. Patients will be instructed to bring their diary and all study drug bottles to each 
follow-up clinic visit so that the diary can be reviewed by study personnel and a capsule count performed to ensure dosing compliance. 
v 
Collect bone marrow at CR for determination of MRD (central lab assessment)  
w 
Long-term follow up for survival 2 years: Year 1- monthly contacts (±7 days) starting 1 month after completion of EOS; Year 2- contacts every 
other month for the following: date of death, date of relapse, or continued remission 
x   PET scan to rule out Richter’s Transformation to be completed within 14 days of first dose 
y 
TLS labs to be assessed at baseline (predose) and at 6 hours and 24 hours post dose (real-time [STAT] review) in patients at high risk for TLS 
(ie, SDWLHQWVZLWKDQ\/1FPRU$/& î 109/DQGDQ\/1 cm) 


Protocol No. TP-0903-102 Amendment 2 
 
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APPENDIX B – ECOG PERFORMANCE STATUS SCALE 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* 
The ECOG Performance Status is in the public domain, therefore available for public use. To duplicate the 
scale, please cite the reference below and credit the Eastern Cooperative Oncology Group, Robert Comis, 
MD, Group Chair. 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-55. 
Available at: http://www.ecog.org/general/perf_stat.html (accessed 29 January 2018). 
 
 


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APPENDIX C – 2018 IWCLL GUIDELINES GRADING SCALE FOR HEMATOLOGIC 
TOXICITY  
Gradea 
Decrease in Plateletsb or Hbc (nadir) 
from Baseline Value (%) 
Absolute Neutrophil 
Count/μLd (nadir) 
0 
No change to 10% 
,000 
1 
11%-24% 
,500 and <2,000 
2 
25%-49% 
,000 and <1,500 
3 
50%-74% 
DQG,000 
4 
 
<500 
From the 2018 IWCLL Guidelines [25]. 
a 
Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as a result 
of toxicity at any level of decrease from baseline will be recorded as grade 5. 
b 
Platelet counts must be below normal levels for grades 1-4. If, at any level of decrease the 
platelet count is <20,000/μL, this will be considered grade 4 toxicity, unless a severe or life-
threatening decrease in the initial platelet count (eg, 20,000/μL) was present baseline, in which 
case the patient is not evaluable for toxicity referable to platelet counts. 
c 
Hb levels must be below normal levels for grades 1-4. Baseline and subsequent Hb 
determinations must be performed before any given transfusions. The use of erythropoietin is 
irrelevant for the grading of toxicity, but should be documented. 
d 
If the absolute neutrophil count (ANC) reaches <1,000/μL, it should be judged to be grade 3 
toxicity. Other decreases in the white blood cell count, or in circulating granulocytes, are not to 
be considered, since a decrease in the white blood cell count is a desired therapeutic end point. 
A gradual decrease in granulocytes is not a reliable index in CLL for stepwise grading of toxicity. 
If the ANC was <1,000/μL prior to therapy, the patient is not evaluable for toxicity referable to 
the ANC. The use of G-CSF is irrelevant for the grading of toxicity but should be documented. 
 
 
 


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APPENDIX D – NCI COMMON TERMINOLOGY CRITERIA AND GRADING FOR 
ADVERSE EVENTS WHERE THE NCI CTCAE CRITERIA ARE NOT APPLICABLE 
View the NCI CTCAE v5.0 criteria electronically at the following Web site: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Qui
ck_Reference_8.5x11.pdf  
The study manual includes a copy of the NCI-CTCAE. 
Grading for adverse events where the NCI Common Toxicity Criteria are not applicable: 
GRADE 1 – Mild: 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
GRADE 2 – Moderate: 
Minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADLa 
GRADE 3 – Severe: 
Medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADLb 
GRADE 4 – Life 
Threatening: 
Life-threatening consequences; urgent intervention 
indicated 
GRADE 5 – Fatal: 
Death related to AE 
a Instrumental activities of daily living (ADLs) refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.  
b Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
 


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APPENDIX E – LABORATORY TESTS 
Hematology 
x 
Complete 
blood 
count 
with manual differential 
x 
Platelet count  
Full Serum 
Chemistry  
x 
Blood urea nitrogen 
x 
Phosphorus 
x 
Magnesium 
x 
Lactate dehydrogenase 
x 
Creatinine 
x 
Uric acid 
x 
Total protein 
x 
Albumin 
x 
Calcium 
x 
Glucose 
x 
Total bilirubin 
x 
Alkaline phosphatase 
x 
Aspartate 
aminotransferase 
x 
Alanine 
aminotransferase 
x 
Electrolytes (sodium, 
potassium, chloride, and 
bicarbonate) 
TLS Labs* 
x 
Uric acid 
x 
Potassium  
x 
Phosphate  
x 
Calcium 
x 
Creatinine 
Immunoglobulin 
testing 
x 
Serum immunoglobulin 
x 
Direct Antiglobulin 
x 
Serum ß2-microglobulin 
Coagulation 
x 
Prothrombin time 
x 
Activated partial 
thromboplastin time 
Urinalysis 
x 
Color 
x 
Specific gravity 
x 
pH 
x 
Bilirubin 
x 
Ketones 
x 
Glucose 
x 
Occult blood (hemoglobin) 
x 
Leukocyte esterase 
x 
Protein 
x 
Urobilinogen 
x 
Nitrites 
x 
White blood cells 
x 
Red blood cells 
x 
Casts, crystals, bacteria 
Cytogenetics and 
karyotyping 
x 
Molecular cytogenetics (FISH) for del(13q), del(11q), del(17p), 
add(12) in peripheral blood lymphocytes 
x 
Conventional karyotyping in peripheral blood lymphocytes (with 
specific stimulation) 
x 
TP53 mutation status 
x 
IGHV mutational status 
Pharmacodynamic 
Tests 
x 
Peripheral blood for chronic lymphocytic leukemia burden and 
minimum residual disease 
x 
Blood for exploratory pharmacodynamic and other biomarkers 
Other Tests 
x 
Pregnancy test (urine or serum determination of beta-human 
chorionic gonadotropin in females of childbearing potential) 
*Real-time [STAT] review required for assessment of TLS labs. 


Protocol No. TP-0903-102 Amendment 2 
 
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APPENDIX F – RESPONSE CRITERIA 
Below is a summary of the IWCLL guidelines 2018 that can be utilized as a quick reference 
for this study. If there are items not outlined below, further detail and clarification can be 
obtained from the referenced Blood journal article authored by Hallek et al [25]. 
 
GROUP 
PARAMETER 
CR 
PR 
PD 
SD 
A 
Lymph nodes 
1RQH.5 cm 
'HFUHDVH 
(from baseline) a 
,QFUHDVH
from baseline or 
from response 
Change of –WR 
 
Liver and/or 
spleen size b 
Spleen size 
 cm; liver 
size normal 
'HFUHDVH
(from baseline) 
,QFUHDVH
from baseline or 
from response 
Change of –
WR 
&RQVWLWXWLRQDO 
V\PSWRPV 
None 
Any 
Any 
Any 
&LUFXODWLQJ
O\PSKRF\WHFRXQW 
Normal 
'HFUHDVH
from baseline 
,QFUHDVH
over baseline 
Change of –
WR 
B 
3ODWHOHWFRXQW 
,O 
,ORU
LQFUHDVHRYHU
baseline 
'HFUHDVHRI
from baseline 
VHFRQGDU\WR CLL 
Change of –WR
 
Hemoglobin 
.JGO 
XQWUDQVIXVHG
DQGZLWKRXW
HU\WKURSRLHWLQ 
 g/dl or 
LQFUHDVH over 
baseline 
'HFUHDVHRI g/dl 
from baseline 
VHFRQGDU\WR&// 
,QFUHDVH. g/dl 
or RYHU
baseline, or 
GHFUHDVH g/dl 
Marrow 
1RUPRFHOOXODU
no CLL cells, 
no B-lymphoid 
QRGXOHV 
Presence of CLL 
cells, or of 
B-O\PSKRLGQRGXOHV
RUQRW done 
Increase of CLL 
FHOOVE\RQ
VXFFHVVLYHbiopsies 
No change in 
PDUURZLQILOWUDWH 
a 
Sum of the products of 6 or less lymph nodes (as evaluated by CT scans and physical exam in clinical trials, 
or by physical exam in general practice). 
b 
Spleen size is considered normal if < 13 cm. There is not firmly established, international consensus of the 
size of a normal liver; therefore, liver size should be evaluated by imaging and manual palpation in clinical 
trials and be recorded according to the definition used in a study protocol. 
CR = complete remission: all of the criteria have to be met  
PR = partial remission: for a PR at least 1 of the parameters of group A and 1 parameter of group B need to 
improve if previously abnormal. If only one parameter of both groups A and B is abnormal prior to therapy, 
only 1 needs to improve  
PD = progressive disease: at least one of the above criteria of group A or group B has to be met;  
SD = stable disease: all of the above criteria have to be met. Constitutional symptoms alone do not define PD. 
 
 


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APPENDIX G – CYP2C19 SUBSTRATES, INDUCERS, AND INHIBITORS 
Physicians should be aware of the possibility of drug interactions when TP-0903 is coadministered with drugs that are inhibitors or 
inducers of CYP2C19. Physicians should refer to the products label and to the drug interaction website provided below. The website 
listing 
cytochrome 
P450 
inhibitors 
and 
inducers 
is 
updated 
on 
an 
ongoing 
basis 
and 
can 
be 
found 
at 
http://medicine.iupui.edu/clinpharm/ddis/main-table. Below is a snapshot of the website as of 31 January 2016. Attention should be 
focused on the 2C19 column. Please note that the website also lists substrates of CYP2C19. 
Cytochrome P450 Drug Interaction Table 
SUBSTRATES 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A4,5,7 
amitriptyline 
caffeine 
clomipramine 
clozapine 
cyclobenzaprine 
estradiol 
fluvoxamine 
haloperidol 
imipramine 
NDeMe 
mexilletine 
naproxen 
olanzapine 
ondansetron 
phenacetinÖ 
acetaminophenÖ 
NAPQI 
propranolol 
riluzole 
ropivacaine 
tacrine 
theophylline 
tizanidine 
verapamil 
(R)warfarin 
zileuton 
zolmitriptan 
bupropion 
cyclophosphamide 
efavirenz 
ifosfamide 
methadone 
paclitaxel 
torsemide 
amodiaquine 
cerivastatin 
repaglinide 
NSAIDs: 
diclofenac 
ibuprofen 
lornoxicam 
meloxicam 
S-naproxenÖNor 
piroxicam 
suprofen 
 
Oral 
Hypoglycemic 
Agents: 
tolbutamide 
glipizide 
 
Angiotensin II Blockers: 
losartan 
irbesartan 
 
Sulfonylureas: 
glyburide 
glibenclamide 
glipizide 
glimepiride 
tolbutamide 
amitriptyline 
celecoxib 
fluoxetine 
fluvastatin 
glyburide 
nateglinide phenytoin--
4-OH2 rosiglitazone 
tamoxifen 
Proton Pump Inhibitors: 
lansoprazole 
omeprazole 
pantoprazole 
rabeprazole 
 
Antiepileptics: 
diazepamÖNor  
phenytoin(O) 
S-mephenytoin 
phenobarbitone 
amitriptyline 
carisoprodol 
citalopram 
chloramphenicol 
clomipramine 
cyclophosphamide 
hexobarbital 
imipramine N-DeME 
indomethacin 
R-mephobarbital 
moclobemide 
nelfinavir 
nilutamide 
primidone 
progesterone 
proguanil 
propranolol teniposide 
R-warfarinÖ8-OH  
Beta Blockers: 
carvedilol 
S-metoprolol 
propafenone 
timolol 
 
Antidepressants: 
amitriptyline 
clomipramine 
desipramine 
imipramine 
paroxetine 
 
Antipsychotics: 
haloperidol 
perphenazine 
risperidoneÖ9OH 
thioridazine 
zuclopenthixol 
alprenolol 
amphetamine 
aripiprazole 
atomoxetine 
bufuralol1 
chlorpheniramine 
chlorpromazine 
codeine (ÖO-des-
Me) 
debrisoquine 
dexfenfluramine 
dextromethorphan 
duloxetine 
Anesthetics: 
enflurane 
halothane 
isoflurane 
methoxyflurane 
sevoflurane 
acetaminophenÖ 
NAPQI 
aniline2 
benzene 
chlorzoxazone 
ethanol 
N,N-dimethyl 
formamide 
theophyllineÖ 
8OH  
Macrolide 
antibiotics: 
clarithromycin 
erythromycin 
(not 
3A5) 
NOT azithromycin 
telithromycin 
 
Antiarrhythmics: 
quinidineÖ3OH 
(not 3A5) 
 
Benzodiazepines: 
alprazolam 
diazepamÖ3OH 
midazolam 
triazolam 
 
Immune 
Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
Prokinetic: 
cisapride 
 
Antihistamines: 


Protocol No. TP-0903-102 Amendment 2 
 
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1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A4,5,7 
torsemide 
S-warfarin 
encainide  
flecainide 
fluoxetine 
fluvoxamine 
lidocaine 
metoclopramide 
methoxy-
amphetamine 
mexilletine 
minaprine 
nebivolol 
nortriptyline 
ondansetron 
oxycodone 
perhexiline 
phenacetin 
phenformin 
promethazine 
propranolol 
sparteine 
tamoxifen 
tramadol 
venlafaxine 
astemizole 
chlorpheniramine 
terfenadine 
 
Calcium 
Channel 
Blockers: 
amlodipine 
diltiazem 
felodipine 
lercanidipine 
nifedipine2 
nisoldipine 
nitrendipine 
verapamil 
 
HMG 
CoA 
Reductase 
Inhibitors: 
atorvastatin 
cerivastatin 
lovastatin 
NOT pravastatin 
simvastatin 
 
Steroid 6beta-OH: 
estradiol 
hydrocortisone 
progesterone 
testosterone 
 
Miscellaneous: 
alfentanyl 
aprepitant 
aripiprazole 
buspirone 
cafergot 
caffeineÖTMU 
cilostazol 
cocaine 
codeine-N-
demethylation 
dapsone 
dexamethasone 
dextromethorphan 
docetaxel 
domperidone 
eplerenone 
fentanyl 


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1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A4,5,7 
finasteride 
gleevec 
haloperidol 
irinotecan 
LAAM 
lidocaine 
methadone 
nateglinide 
ondansetron 
pimozide 
propranolol 
quetiapine 
quinine 
risperidone 
NOT rosuvastatin 
salmeterol 
sildenafil 
sirolimus 
tamoxifen 
taxol 
terfenadine 
trazodone 
vincristine 
zaleplon 
ziprasidone 
zolpidem 
 
 
 


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INHIBITORS 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A4,5,7 
fluvoxamine 
ciprofloxacin 
cimetidine 
amiodarone 
fluoroquinolones 
furafylline 
interferon 
methoxsalen 
mibefradil 
thiotepa 
ticlopidine 
gemfibrozil 
trimethoprim 
glitazones 
montelukast 
quercetin 
fluconazole 
amiodarone 
fenofibrate 
fluvastatin 
fluvoxamine 
isoniazid 
lovastatin 
phenylbutazone 
probenicid 
sertraline 
sulfamethoxazole 
sulfaphenazole 
teniposide 
voriconazole 
zafirlukast 
PPIs: 
lansoprazole 
omeprazole 
pantoprazole 
rabeprazole 
chloramphenicol 
cimetidine 
felbamate 
fluoxetine 
fluvoxamine 
indomethacin 
ketoconazole 
modafinil 
oxcarbazepine 
probenecid 
ticlopidine 
topiramate 
bupropion 
fluoxetine 
paroxetine 
quinidine 
duloxetine 
terbinafine 
amiodarone 
cimetidine 
sertraline 
celecoxib 
chlorpheniramine 
chlorpromazine 
citalopram 
clemastine 
clomipramine 
cocaine 
diphenhydramine 
doxepin 
doxorubicin 
escitalopram 
halofantrine 
histamine H1 
receptor antagonists 
hydroxyzine 
levomepromazine 
methadone 
metoclopramide 
mibefradil 
midodrine 
moclobemide 
perphenazine 
ranitidine 
red—haloperidol 
ritonavir 
ticlopidine 
tripelennamine 
diethyldithiocarbamate 
disulfiram 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
saquinavir 
telithromycin 
aprepitant 
erythromycin 
fluconazole 
grapefruit juice 
verapamil 
diltiazem 
cimetidine 
amiodarone 
NOT azithromycin 
chloramphenicol 
delaviridine 
diethyl-
dithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine  
star fruit 
voriconazole 
 
 
 


Protocol No. TP-0903-102 Amendment 2 
 
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TOLERO PHARMACEUTICALS, INC 
INDUCERS 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A4,5,7 
broccoli 
brussel sprouts 
chargrilled meat 
insulin 
methylcholanthrene 
modafinil 
nafcillin 
beta-naphthoflavone 
omeprazole 
tobacco 
phenobarbital 
rifampin 
rifampin 
rifampin 
secobarbital 
carbamazepine 
norethindrone 
NOT pentobarbital 
prednisone 
rifampin 
dexamethasone 
rifampin 
ethanol 
isoniazid 
HIV Antivirals: 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
efavirenz 
glucocorticoids 
modafinil 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's wort 
troglitazone 
The entire content of this site is protected by International and United States of America copyright laws. © 2003; Cytochrome P450 Drug Interaction Table. 
Source: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). 
Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/ (accessed 07 March 2018). 
 


Protocol No. TP-0903-102 Amendment 2 
 
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APPENDIX H – BASELINE DISEASE ASSESSMENTS ACCORDING TO 2018 IWCLL 
GUIDELINES 
Below is a summary of the baseline disease assessments per IWCLL guidelines 2018 that 
can be utilized as a quick reference for this study. If there are items not outlined below, further 
detail and clarification can be obtained from the referenced Blood journal article authored by 
Hallek et al [25]. 
Diagnostic test 
Clinical Trial 
Tests to Establish the Diagnosis 
 
x Complete blood count and differential count 
Always 
x Immunophenotyping of peripheral blood lymphocytes 
Always 
Assessments Prior to Treatment 
 
x History and physical, performance status 
Always 
x Complete blood count and differential count 
Always 
x Marrow aspirate and biopsy 
Desirable 
x Serum chemistry, serum immunoglobulin, and direct antiglobulin test 
Always 
x Infectious disease status 
Always 
Additional Tests Prior to Treatment 
 
x Molecular cytogenetics (FISH) for del(13q), del(11q), del(17p), add(12) in 
peripheral blood lymphocytes 
Always 
x Conventional karyotyping in peripheral blood lymphocytes (with specific 
stimulation) 
Desirable 
x TP53 mutation 
Always 
x IGHV mutational status 
Always 
x Serum ß2-microglobulin 
Always 
x CT scan of chest, abdomen, and pelvis 
Desirable 
Abbreviations: FISH, fluorescence in situ hybridization. 
* conventional karyotyping in peripheral blood lymphocytes (with specific stimulation) may be useful prior to 
therapy if established methodology is available. 
 


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APPENDIX I – PATIENT DOSING DIARY 
PATIENT ID:____________PATIENT INITIALS:____________ 
ASSIGNED COHORT/DOSE:_____________GROUP  ________  
CYCLE 
___ 
DATE 
(DD MMM YYYY) 
TIME OF 
DOSING 
__ __: __ __ AM 
# and STRENGTH of CAPSULES TAKEN 
Ibrutinib Dose 
COMMENTS 
(Document missed dose/reason; document 
vomiting after dosing and time) 
1 mg 
4 mg 
16 mg 
25 mg 100 mg 
_______ mg 
Example: 
01 Jan 2017 
09:24 
0 
2 
0 
1 
0 
420 
Vomited 2 hrs after dosing 
WEEK 1 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
WEEK 2 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
WEEK 3 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
WEEK 4 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
'D\ 
 
 
 
 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
16.1.9 Documentation of Statistical Methods 
TP-0903-102 – Ph1/Ph2 Previously Treated CLL 
FINAL 
TP-0903 (Dubermatinib) 
June-2020 
Confidential/Proprietary Property of Tolero Pharmaceuticals 
16 APPENDICES 
16.1 STUDY INFORMATION 
16.1.9 DOCUMENTATION OF STATISTICAL METHODS 
1 of 38




3Tolero Pharmaceuticals 
Statistical Analysis Plan 
Protocol: TP-0903-102 
Version: 1.0  (Dated 13APR2020) 
Confidential/Proprietary Property of Tolero Pharmaceuticals  
Page 1 of 36 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Combined Phase 1/2 Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity 
of TP-0903 in Patients with Previously Treated Chronic 
Lymphocytic Leukemia (CLL) 
Sponsor 
Tolero Pharmaceuticals, Inc. 
3900 N Traverse Mountain Blvd, Suite 100 
Lehi, UT 84043 
Protocol Number 
TP-0903-102 
IND Number 
139577 
Investigational Product 
TP-0903 
Phase of Development 
Phase 1 / 2 
Analysis Plan Version 
Version 1.0 
Analysis Plan Date 
April 13, 2020 
The information in this document is confidential and proprietary to Vantage Data Designs (VDD) and its Clients. The 
information may only be used by the entities to which it was disclosed. The information must not be disclosed to any third 
parties without the prior written consent of VDD.
3 of 38


3Tolero Pharmaceuticals 
Statistical Analysis Plan 
Protocol: TP-0903-102 
Version: 1.0  (Dated 13APR2020) 
Confidential/Proprietary Property of Tolero Pharmaceuticals  
Page 2 of 36 
STATISTICAL ANALYSIS PLAN APPROVAL 
4 of 38


3Tolero Pharmaceuticals  
 
Statistical Analysis Plan 
Protocol: TP-0903-102 
 
Version: 1.0  (Dated 13APR2020) 
 
Confidential/Proprietary Property of Tolero Pharmaceuticals  
Page 3 of 36 
TABLE OF CONTENTS 
Section 
Page 
1. INTRODUCTION ...............................................................................................................8 
2. OVERVIEW OF STUDY DESIGN ....................................................................................9 
3. STUDY OBJECTIVES AND ENDPOINTS .....................................................................11 
3.1 Study Objectives ........................................................................................................11 
3.1.1 Phase 1 Primary Objectives ..............................................................................11 
3.1.2 Phase 1 Secondary Objectives ..........................................................................12 
3.1.3 Phase 1 Exploratory Objectives ........................................................................12 
3.1.4 Phase 2 Primary Objectives ..............................................................................12 
3.1.5 Phase 2 Secondary Objectives ..........................................................................12 
3.1.6 Phase 2 Exploratory Objectives ........................................................................13 
3.2 Study Endpoints .........................................................................................................13 
3.2.1 Safety Endpoints ...............................................................................................13 
3.2.2 Efficacy Endpoints ............................................................................................13 
3.2.3 Pharmacokinetic (PK) Endpoints ......................................................................14 
3.2.4 Pharmacodynamic (PD) Endpoints ...................................................................14 
4. SAMPLE SIZE JUSTIFICATION ....................................................................................14 
5. RANDOMIZATION, BLINDING, AND REPLACEMENT OF 
PATIENTS .........................................................................................................................16 
6. DEFINITIONS OF PATIENT POPULATIONS TO BE 
ANALYZED ......................................................................................................................17 
7. PLANNED ANALYSES ...................................................................................................17 
7.1 Interim Analysis ........................................................................................................17 
7.2 Final Analysis ............................................................................................................18 
8. DATA PRESENTATION AND HANDLING ..................................................................18 
8.1 General Summary Table and Individual Patient Data Listing Considerations ..........18 
8.2 General Summary Table and Patient Data Listing Format Considerations ..............18 
8.3 Data Management ......................................................................................................18 
8.4 Data Presentation Conventions ..................................................................................19 
8.5 Treatment Comparisons .............................................................................................19 
8.6 Definitions, Computations, Derived Data .................................................................19 
9. GENERAL CONSIDERATIONS FOR DATA ANALYSES ..........................................21 
9.1 Multicenter Studies ....................................................................................................21 
9.2 Other Strata and Covariates .......................................................................................21 
9.3 Examination of Subgroups ........................................................................................22 
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9.4 Multiple Comparisons and Multiplicity ....................................................................22 
9.5 Missing Data and Dropouts .......................................................................................22 
9.5.1 Adverse Events..................................................................................................22 
9.5.2 Concomitant Medications .................................................................................22 
9.5.3 Other Situations .................................................................................................22 
10. STUDY POPULATION ....................................................................................................22 
10.1 Patient Enrollment and Disposition ...........................................................................22 
10.2 Protocol Violations or Deviations .............................................................................23 
10.3 Demographics ............................................................................................................23 
10.4 Baseline Characteristics .............................................................................................23 
10.5 Past Medical Therapies / Surgeries for Cancer Related Indications .........................23 
10.6 Concomitant Medications ..........................................................................................23 
10.7 Study Drug Administration and Exposure ................................................................23 
11. EFFICACY ANALYSIS ...................................................................................................24 
11.1 Primary Endpoint .......................................................................................................24 
11.2 Secondary Endpoints .................................................................................................25 
12. SAFETY ANALYSIS ........................................................................................................26 
12.1 Treatment Emergent Adverse Events ........................................................................26 
12.2 Serious Adverse Events .............................................................................................27 
12.3 Adverse Events Leading to Discontinuation from Study ..........................................27 
12.4 Deaths Due to Adverse Event ....................................................................................27 
12.5 Dose Limiting Toxicity (DLT) and Maximum Tolerate Dose (MTD) .....................27 
12.6 Clinical Laboratory Tests ..........................................................................................27 
12.6.1 Hematology .......................................................................................................27 
12.6.2 Chemistry ..........................................................................................................28 
12.6.3 Coagulation .......................................................................................................28 
12.6.4 Urinalysis ..........................................................................................................28 
12.6.5 Immunoglobulin ................................................................................................28 
12.6.6 TS Labs (only if subject is indicated as at high-risk for TLS) ..........................28 
12.7 Vital Signs and Weight ..............................................................................................28 
12.8 12-Lead Electrocardiogram (ECG) ...........................................................................29 
12.9 ECOG Performance Status ........................................................................................29 
12.10 
Physical Examination and Pregnancy Test .......................................................29 
13. PHARMACOKINETIC (PK) ANALYSIS .......................................................................30 
14. PHARMACODYNAMIC (PD) ANALYSIS ....................................................................30 
15. COMMITMENT TO GOOD STATISTICAL PRACTICE ..............................................31 
15.1 Definition of Good Statistical Practice ......................................................................31 
15.2 Data Management and Use of CDISC Standards ......................................................31 
15.3 Testing/Validation Plan and Software System ..........................................................31 
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16. STATISTICAL ANALYSIS CHANGES FROM THE 
PROTOCOL ......................................................................................................................31 
17. REFERENCES ..................................................................................................................32 
18. SCHEDULE OF ASSESSMENTS ....................................................................................34 
 
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ABBREVIATIONS AND DEFINITIONS 
ADaM 
analysis data model  
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
BOR 
best objective response 
bpm 
beats per minute 
BP 
blood pressure 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DLT 
dose limiting toxicity 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EDC 
electronic data capture 
EOS 
end-of-study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HR 
heart rate 
ICH 
International Committee for Harmonization 
IP 
Investigational Product 
ITT 
intent to treat 
IU 
international units 
IWCLL 
International Workshop on CLL 
K-M 
Kaplan-Meier 
mmHg 
millimeters of mercury 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute  
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
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PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
PPT 
partial prothrombin time 
QTcF 
corrected QT interval (using Fridericia’s correction formula) 
RP2D 
recommended Phase 2 dose 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System (software) 
SBP 
systolic blood pressure 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UNK 
unknown 
WHO-DD 
World Health Organization - Drug Dictionary 
 
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1. 
INTRODUCTION 
The Statistical Analysis Plan (SAP) describes the data analysis specifications for Tolero 
Pharmaceuticals. protocol TP-0903-102 titled: “A Combined Phase 1/2 Study to Investigate 
the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of TP-0903 in 
Patients with Previously Treated Chronic Lymphocytic Leukemia (CLL)”. It details the 
inferential statistical methodology to be used in analyzing study data and outlines the 
statistical programming specifications, tables, figures, and listings. It describes the variables 
and populations, anticipated data transformations and manipulations, and other details of the 
analyses not provided in the clinical study protocol. 
This version of the SAP was prepared in accordance with the protocol TP-0903-102 
Amendment 2 dated November 13, 2018. Other related documents are the annotated patient 
case report forms (version 1.0, 16AUG2018) and the corresponding Medrio electronic data 
capture (EDC) data dictionary.  
The SAP will be finalized prior to database lock and describes the statistical analysis as it is 
foreseen when the study is being planned. If circumstances should arise during the study 
rendering this analysis inappropriate, or if in the meantime improved methods of analysis 
should come to light, different analyses may be made. Any deviations from the SAP after 
database lock, reasons for such deviations, and all alternatives or additional statistical 
analyses that may be performed will be described in a SAP Addendum and in the clinical 
study report. This SAP supersedes the statistical considerations identified in the protocol. 
NOTE: On January 14, 2020 the investigative sites were notified of the decision by 
Tolero Pharmacetucial to close this study due to lack of accrual. This SAP will reflect 
the latest protocol (Amendment 2) language along with the current status where 
appropriate.  
Enrollment status as of January 14, 2020: 
x Phase 1: 3 patients enrolled. 
 Group 1: one patient enrolled at the TP-0903 25 mg flat dose. 
 Group 2: two patients enrolled. Both were at the TP-0903 20 mg 
flat dose group in combination with ibrutinib at the same dose that 
they were receiving immediately prior to study enrollment. 
x Phase 2: no patients enrolled 
This study terminated enrollment before MTD and RP2D was identified.  
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Effiacy endpoints will not be analyzed via statistical methods due to low enrollment in 
Phase 1 and no enrollment in Phase 2. Patient listings, patient profiles, and swimmers 
plot will be used to display the efficacy data.  
Safety data will be displayed using patient listings and patient profiles.  
2. 
OVERVIEW OF STUDY DESIGN 
Experimental Design:  
This is a combined Phase 1/2 study of oral TP-0903 in patients with previously treated 
CLL/SLL. In both Phase 1 and Phase 2, study participants will be assigned to one of two 
defined patient groups: 
x Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who are intolerant to, or have 
progressed on, B-cell receptor antagonists and/or BCL-2 antagonists  
x Group 2 (TP-0903 and ibrutinib combination therapy): Patients with CLL/SLL who have 
progressed on ibrutinib, yet the treating provider considers continuation of ibrutinib 
therapy to be in the best interest of the patient.  
Both groups of patients will be treated identically with TP-0903 and will undergo the same 
study assessments. 
Phase 1 
Current Status: As of January 14, 2020, 3 patients were enrolled the Phase 1 portion of 
this study. 
Planned: Patients will be enrolled in Group 1 and Group 2 in cohorts of 3 to 6 patients 
simultaneously. Group 2 will start at one dose level below the Group 1 starting dose. In each 
group, escalation of the TP-0903 dose will follow a standard 3+3 design with sequential 
cohorts of three patients treated with incrementally higher doses of TP-0903 until a dose-
limiting toxicity (DLT) is observed and the maximum tolerated dose (MTD) is established. 
Once the first patient at a dose level is enrolled, the second and third patients may be enrolled 
after 3 weeks if the initial patient has not experienced a DLT or any unacceptable toxicity. 
If 1 of 3 patients in a cohort experiences a DLT, up to 3 additional patients will be treated at 
that dose level. If no additional DLTs are observed in the expanded 3- to 6-patient cohort 
within 28 days after the last patient was first dosed, the dose will be escalated in a new cohort 
of 3 patients. If 2 or more of 3 to 6 patients at a given dose level experience a DLT during the 
first cycle, then the MTD will have been exceeded and up to a total of 6 patients will be 
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treated at the previous lower dose level. If 0 or 1 of 6 patients experiences a DLT at this 
previous lower dose level, this dose will be declared the MTD. 
The MTD is defined as WKHGRVHDWZKLFKRISDWLHQWVH[SHULHQFHD'/7GXULQJ&\cle 1 
with the next higher dose having at least 2 of 3 to 6 patients experiencing a DLT during 
Cycle 1. Once the MTD or preliminary RP2D is identified, an expansion cohort of up to 6 
patients will be enrolled in each patient group to confirm safety/suitability of the preliminary 
RP2D, to collect additional biomarker data, and to further explore efficacy. 
Additional dose levels, schedules, or disease indications of TP-0903 may be explored, as 
appropriate, based on the modulation of key biomarkers and the safety profile and clinical 
signals of activity. 
Phase 2 
Current Status: As of January 14, 2020, no patients were enrolled the Phase 2 portion 
of this study. 
Planned: In Phase 2, patients will be enrolled in Group 1 (TP-0903 monotherapy) and Group 
2 (TP-0903 combination therapy with ibrutinib) based on the Simon 2-stage design. In Stage 
1, up to 13 patients will be enrolled into each patient group (total of 26 patients). If there are 
no responses among these 13 patients in each group, the study will be stopped. Otherwise, 
Stage 2 will open to enroll 14 additional patients in each group for a total of 27 patients per 
group. If 4 or more responses are observed among 27 patients, the conclusion will be that the 
study treatment is worthy of further investigation. When the true response rate of 20% 
(alternative hypothesis) is tested against the null hypothesis response rate of 5%, this design 
yields a Type I error rate of 0.05 and power of 80%.  
If both patient groups enroll through Stage 2, it is anticipated that the total enrollment for 
Phase 2 will be 54 patients. 
Any patient who withdraws from the study for treatment-related toxicity prior to being 
evaluated for response in Phase 2 will be considered a nonresponder. Patients who drop out 
of the study for other reasons prior to being assessed for response will be considered 
unevaluable and may be replaced. Enrollment in either patient group may be stopped at any 
SRLQWRQFHSDWLHnts have had a response to treatment, but the maximum enrollment in each 
patient group in Phase 2 will be 27 evaluable patients. 
Study treatment:  
Phase 1: 
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Group 1: TP 0903 (monotherapy). The starting dose for TP 0903 (monotherapy) will 
be a 25-mg flat dose. The study drug will be administered orally once daily for 28 
days (each cycle is 28 days; no drug-free period).  
NOTE: As of January 14, 2020, one patient was enrolled in Group 1 at 
the TP-0903 25 mg flat dose.  
Group 2: TP-0903 and ibrutinib combination therapy. The starting dose of TP-0903 
will be a 20-mg flat dose. TP-0903 will be administered orally once daily for 28 days 
(each cycle is 28 days; no drug-free period). Patients will also receive ibrutinib at the 
same dose that they were receiving immediately prior to study enrollment.  
NOTE: As of January 14, 2020, two patients were enrolled in Group 2. 
Both were at the TP-0903 20 mg flat dose group in combination with 
ibrutinib at the same dose that they were receiving immediately prior to 
study enrollment. 
Phase 2: 
Group 1: TP 0903 (monotherapy) will be ther recommended Phase 2 dose (RP2D) 
determined during Phase 1. 
Group 2: TP-0903 and ibrutinib combination therapy will be ther recommended 
Phase 2 dose (RP2D) determined during Phase 1. 
NOTE: The Phase 2 portion of this study did not enroll any patients.  
Number of patients planned:   
Up to 108 patients (up to 27 patients in each group (Group 1 and Group 2) in both Phase 1 
(n=54) and Phase 2 (n=54). 
NOTE: As of January 14, 2020, Phase 1 Group 1 enrolled one patient and Phase 
1 Group 2 enrolled two patients. Phase 2 did not enroll any patients.  
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 Phase 1 Primary Objectives 
x To characterize the safety and toxicity profile of TP-0903 when administered orally 
once daily for 28 days (each cycle is 28 days; no drug-free period) in the following 
patient groups: 
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o Group 1 (TP-0903 monotherapy): those with CLL/SLL who are intolerant to, 
or have had progressive disease on B-cell receptor antagonists, BCL-2 
antagonists or other investigational treatments for CLL/SLL   
o Group 2 (TP-0903 and ibrutinib combination therapy): those with CLL/SLL 
who have progressed on ibrutinib, yet the treating provider considers 
continuation of ibrutinib therapy to be in the best interest of the patient.   
x To determine the Recommended Phase 2 Dose (RP2D) of TP-0903 when 
administered orally on this schedule to the defined patient groups. 
3.1.2 Phase 1 Secondary Objectives 
x To observe patients for any evidence of antileukemic activity of oral TP 0903 by 
determining the Objective Response Rate ([ORR], ie, rate of complete response [CR] 
plus rate of partial response [PR] in the defined patient groups according to guidelines 
set forth by the 2018 International Workshop on CLL (IWCLL)  
x To evaluate the pharmacokinetics (PK) of oral TP-0903 in the defined patient groups. 
3.1.3 Phase 1 Exploratory Objectives 
x To study potential biomarkers relevant to disease and pharmacodynamics (PD) of oral 
TP-0903 in the defined patient groups through assessment of analytes including, but 
not limited to, soluble AXL, AXL expression and phosphorylation, growth arrest 
specific 6 (GAS6), and mesenchymal transcription factors in peripheral blood 
samples and bone marrow. 
3.1.4 Phase 2 Primary Objectives 
x To determine the ORR in the two defined patient groups according to guidelines set 
forth by the 2018 IWCLL. 
3.1.5 Phase 2 Secondary Objectives 
x To determine the Duration of Response (DoR, ie, the time from tumor response to 
disease progression) 
x To determine the Progression-free Survival (PFS, ie, the time from first dose to 
objective tumor progression or death) 
x To determine the rate of Overall Survival (OS, ie, the time from first dose to death 
from any cause). 
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3.1.6 Phase 2 Exploratory Objectives 
x To study potential biomarkers relevant to disease and pharmacodynamics (PD) of oral 
TP-0903 in the defined patient groups through assessment of analytes including, but 
not limited to, soluble AXL, AXL expression and phosphorylation, growth arrest 
specific 6 (GAS6), and mesenchymal transcription factors in peripheral blood 
samples and bone marrow. 
3.2 
Study Endpoints  
3.2.1 Safety Endpoints 
Safety will be monitored from the time of the first dose until 30 days after the last dose of 
TP-0903. During Phase 1, the safety endpoints will be evaluated after Cycle 1. The dose 
escalation committee will have access to complete safety profiles of all patients receiving TP 
0903 to enable decision making. 
The primary safety endpoint is to assess the tolerance and toxicity of continuous orally 
administered TP-0903 through evaluation of physical examinations, vital signs, laboratory 
parameters, solicited and unsolicited adverse events (AEs) including DLTs, and all causes of 
mortality up to 30 days from the last dose in both phases of the study.  
Overall safety profile will be characterized by type, frequency, severity, seriousness, timing, 
duration, and relationship of study drug to AEs and laboratory abnormalities. 
Treatment-emergent adverse events (TEAEs), namely, those with initial onset or that worsen 
in severity after the first dose of TP-0903 will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 21.0 or higher and graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
All DLTs will be reported and the MTD and RP2D identified.  
NOTE: This study terminated enrollment before MTD and RP2D was identified.  
3.2.2 Efficacy Endpoints 
The primary efficacy endpoint of the Phase 2 study is to determine the ORR (rate of CRs 
plus PRs) in the defined patient groups according to guidelines set forth by the 2018 IWCLL. 
Secondary efficacy endpoints include DoR, PFS, and OS 
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Efficacy assessments will be performed on Day 28 of Cycle 2 and then every even cycle 
thereafter (ie, Cycle 4/Day 28, Cycle 6/Day 28, etc). Response rates will be calculated in 
Stage 1 and Stage 2 as per the Simon 2 stage design. 
NOTE: Effiacy endpoints will not be analyzed via statistical methods due to low 
enrollment in Phase 1 and no enrollment in Phase 2.  
3.2.3 Pharmacokinetic (PK) Endpoints 
Plasma PK analysis of oral TP-0903 will be performed at protocol-specified time points 
during Cycle 1 in all patients enrolled in the Phase 1 study (Section 7.3 of the protocol). 
Known metabolites of TP-0903, if any, may also be evaluated. No PK assessments will be 
conducted during Phase 2. 
Standard plasma PK parameters will be calculated, including: maximum observed plasma 
concentration (Cmax), time to Cmax (peak time) (Tmax), area under the plasma 
concentration curve (AUC) from time 0 to 24 hours (AUC0-24), AUC from time 0 to infinity 
(AUC0 inf), AUC from time 0 to time t (AUCt), half-life (t1/2), and clearance using 
noncompartmental methods (CL). If data permit, dose proportionality and accumulation ratio 
will be estimated in Phase 1 Cycle 1. 
3.2.4 Pharmacodynamic (PD) Endpoints 
Potential biomarker assessments will be evaluated during Phase 1 and Phase 2 (Section 7.4 of 
the protocol). Blood for potential biomarker assessments including, but not limited to, 
soluble AXL, AXL expression and phosphorylation, GAS6 and mesenchymal transcription 
factors.  
4. 
SAMPLE SIZE JUSTIFICATION 
Phase 1 
Current Status: As of January 14, 2020, 3 patients have been enrolled the Phase 
1 portion of this study. 
Planned: Patients will be enrolled for each patient group (TP-0903 monotherapy and 
combination therapy with ibrutinib) in cohorts of 3 to 6 patients. Escalation of the TP-
0903 dose will follow a standard 3+3 design with sequential cohorts of 3 patients 
treated with incrementally higher doses of TP-0903 until a DLT is observed and the 
MTD is established.Based on the standard oncology 3+3 dose escalation design, the 
total number of patients to be enrolled cannot be precisely determined as the sample 
size is dependent upon the observed safety profile, which will determine the number 
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of patients per dose cohort, as well as the number of dose escalations required to 
achieve the MTD. It is anticipated that 12 to 21 patients will be required to achieve 
MTD dose level. Once the MTD or preliminary RP2D is identified, an expansion 
cohort of approximately six patients will be enrolled in each patient group to confirm 
safety/confirm the suitability of the preliminary RP2D, to collect additional 
biomarker data, and to further explore efficacy. It is expected that up to 27 patients 
will be enrolled in each patient group (Group 1: TP-0903 monotherapy and Group 2: 
TP-0903 combination therapy with ibrutinib). 
Phase 2 
Current Status: As of January 14, 2020, no patients have been enrolled the 
Phase 2 portion of this study. 
Planned: The statistical power calculations for each patient group (monotherapy and 
combination therapy) are based on the Simon 2 stage minimax design.  
x Stage 1, up to 13 evaluable patients will be enrolled and treated at the RP2D 
identified in the Phase 1 part of this study. Stage 2 may be initiated at any 
point after confirming a response (CR or PR) in at least one Stage 1 patient. If 
there are no responders among 13 evaluable Stage 1 patients, the study will be 
stopped after Stage 1.  
x Stage 2, 14 patients will be enrolled to bring the total enrollment in Phase 2 
(including Stage 1 patients) to 27 evaluable patients. Stage 2 patients will also 
receive the RP2D dose identified in the Phase 1 study. If 4 or more responses 
are observed in 27 patients, the conclusion will be that the combination 
regimen is worthy of further investigation. When the true response rate of 
20% (alternative hypothesis) is tested against the null hypothesis response rate 
of 5%; this design yields a Type I error rate of 0.05 and power of 80%. 
 If both patient groups (TP 0903 monotherapy and combination therapy with 
ibrutinib) enroll through Stage 2, it is anticipated that the total enrollment for Phase 2 
will be 54 patients (Group 1: TP-0903 monotherapy [n=27] and Group 2: 
combination therapy [n=27]). 
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Since this is an open-label study, blinding is not performed as part of this study design.  
The study will be managed by the Sponsor and/or its designee and all sites must receive 
authorization from the Medical Monitor for enrollment of any eligible patient. Patients will 
be enrolled from all participating centers. 
Patients who are lost to follow-up or withdraw consent for study participation prior to 
administration of study drug may be replaced, at sponsor’s discretion. 
6. 
DEFINITIONS OF PATIENT POPULATIONS TO BE ANALYZED 
This study will have three analysis populations: 
x Intent-to-Treat (ITT) analysis set includes all patients who were enrolled into the 
study. 
x Safety analysis set consists of all patients who received any amount of study 
treatment (TP-0903). 
7. 
PLANNED ANALYSES 
7.1 
Interim Analysis 
For Phase 1, the safety data will be monitored continuously per standard Phase 1 oncology 
practices.  
For Phase 2, since the Simon 2-stage design will be employed, response rate data will be 
assessed after Stage 1 to determine if the study will go forward to Stage 2.  
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NOTE: No patients enrolled in Phase 2, so no interim analysis will take place.  
7.2 
Final Analysis 
The final listings and patient profiles will be conducted once the clinical database has been 
locked. For this study, the database will be locked with three patients enrolled.  
8. 
DATA PRESENTATION AND HANDLING 
8.1 
General Summary Table and Individual Patient Data Listing Considerations 
Due to only 3 patients enrolled and treate, only patient listings and patient profiles will be 
prepared for purposes of an abbreviated clinical study report.  
Listings will also be sorted by group, dose cohort, and patient number. Listings will also 
include visit number, visit date/time and days relative to the initiation of study treatment. 
8.2 
General Summary Table and Patient Data Listing Format Considerations 
The tables, figures and listings will be numbered using a decimal system to reflect main 
levels of unique listings and sub-levels of replicate tables and listings with two digits per 
level (e.g., Table XX.YY.ZZ. …). 
1. The first level number will be consistent with the corresponding Clinical Study 
Report (CSR) appendix in which the listings will appear. For example, the individual 
patient data listings will appear in Appendix 16 (and will be numbered 16.XX.YY).  
2. Each listing title will be complete, accurate and concise. The last line of the title will 
provide the analysis group being summarized (e.g., Safety Population). 
8.3 
Data Management 
All data will be recorded by the site in individual source documents. An eCRF will be 
created by the data management group for recording of the required data in the study 
database. All eCRF information is to be filled in by site staff. If an item is not available or is 
not applicable, this fact should be indicated. Blank spaces should not be present unless 
otherwise directed. 
The study monitor will perform source data verification of data entered into the eCRF and 
raise queries for correction by the site. The data entered into the eCRF will be patient to data 
validation checks for consistency and completeness by the data management group. Data 
queries will then be generated and sent to the investigational site for response before the 
database is locked and released for statistical analysis. 
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o “Study Day x” (where x>0) refers to the number of days from first dosing date 
in Cycle 1. For example, Study Day 1 is Cycle 1 Day 1. 
x Visit Nomenclature: Nominal visits nomenclature on the CRFs and the scheduled 
visit will be used for summary tables. 
o Scheduled visits for the Treatment Period are: “Screening”, “Cycle x Day 1” 
(where x = 1, 2, 3, … 9), Days 1, 5, 8, 15,21,28 (same as day 1 of next cycle) 
or “End of Study”.  
o 30-day follow-up visits is 30 days after the last dose of study drug. 
x Response Criteria: Appendix F of the protocol presents a summary of the IWCLL 
guidelines 2018 that can be utilized as a quick reference for this study. If there are 
items not outlined below, further detail and clarification can be obtained from the 
referenced Blood journal article authored by Hallek et al [25]. 
x The best objective response rate (OOR): The best ORR recorded from the start of the 
treatment until disease progression/recurrence. For data programming purposes, this 
will be taken directly from eCRF dataset OR, variable name ORRESP. 
x Dose Limiting Toxicity (DLT) is defined as any one of the following events observed 
within Cycle 1, regardless of attribution unless clearly and incontrovertibly related to 
the underlying disease or extraneous causes (such as progressive disease): 
o $Q\*UDGHQRQKHPDWRORJLFWR[LFLW\ 
o $Q\*UDGH$(WKDWGRHVQRWUHVROYHWR*UDGHZLWKLQKRXUVZLWKXVHRI
supportive care 
o $Q\$67DQG$/7HOHYDWLRQî8/1DFFRPSDQLHGE\VHUXPELOLUXELQ
OHYHOV!î8/1 
o $Q\*UDGHHOHFWURO\WHGLVWXUEDQFHVHJKyperkalemia, hypophosphatemia, 
hyperuricemia) that do not resolve within <72 hours 
o $Q\*UDGHHOHYDWLRQVLQFUHDWLQLQH 
o Any Grade 5 toxicity 
o Any instance of febrile neutropenia 
x Maximum Tolerated Dose (MTD): If 1 of 3 patients in a cohort experiences a DLT, 
up to 3 additional patients will be treated at that dose level. If no additional DLTs are 
observed in the expanded 3- to 6 patient cohort within 28 days after the last patient 
was first dosed, the dose will be escalated in a new cohort of 3 patients. If 2 or more 
of 3 to 6 patients at a given dose level experience a DLT during the first cycle, then 
the MTD will have been exceeded and up to a total of 6 patients will be treated at the 
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previous lower dose level. If 0 or 1 of 6 patients experiences a DLT at this previous 
lower dose level, this dose will be declared the MTD.  
7KH07'LVGHILQHGDVWKHGRVHDWZKLFKRISDWLHQWVH[SHULHQFHD'/7GXULQJ
Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a 
DLT during Cycle 1. 
x Dose Expansion: Once the MTD or preliminary RP2D is identified, an expansion 
cohort of up to 6 patients will be enrolled in each patient group to confirm 
safety/suitability of the preliminary RP2D, to collect additional biomarker data, and 
to further explore efficacy. 
x 1 year = 365.25 days. Year is calculated as (days / 365.25) and will be rounded to 1 
digit after the decimal point (tenths) for presentation purposes; 
x 1 month = 30.4375 days. Month is calculated as (days / 30.4375) and will be rounded 
to 1 digit after the decimal point (tenths) for presentation purposes; 
x 1 pound = 0.454 kg and 1 kg = 2.2 pounds; 
x 1 inch = 2.54 cm and 1 cm = 0.3937 inches; 
x Body mass index (BMI) calculated as [weight (lbs) / height (in)2] x 703; 
x Age will be calculated in years relative to the date of study consent based on the 
following SAS statement: Age = ([Consent Date - Date of Birth] / 365.25) and will be 
rounded to 1 digit after the decimal point (tenths) for presentation purposes; 
9. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
The listings for the disposition and safety, and efficacy data will be the responsibility of the 
study Biostatistician at Vantage Data Designs. All data in the database will be presented in 
the data listings. Unless otherwise stated, all listings will be sorted by group, dose cohort, 
patient number and assessment date/time. 
The currently supported version of SAS software (9.4 or later) will be used to perform all 
data analyses. The actual SAS version used will be presented in the Clinical Study Report. 
9.1 
Multicenter Studies 
Data from all participating sites will be pooled in the listings.  
9.2 
Other Strata and Covariates 
Not applicable for this study. 
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9.3 
Examination of Subgroups 
Not applicable for this study. 
9.4 
Multiple Comparisons and Multiplicity 
Not applicable for this study. 
9.5 
Missing Data and Dropouts 
Not Applicable. 
9.5.1 Adverse Events 
Not Applicable. 
9.5.2 Concomitant Medications 
Not Applicable. 
9.5.3 Other Situations 
The original data will be presented in the listings. 
10. 
STUDY POPULATION 
All disposition, baseline and demographic listings will be conducted on the Safety 
population. 
10.1 
Patient Enrollment and Disposition 
Enrollment and disposition will be listed for all enrolled patients (defined as those patients 
who signed informed consent form). The patient listing of enrollment will be presented by 
investigator site. The patient disposition listing will include: 
x Patients who were enrolled 
x Patients in Group 1 and Group 2 
x Patients who complete the protocol. 
x Reasons for withdrawal from study 
x Reasons for patients with treatment failure. 
All patients enrolled in the study will be accounted for in the listing. 
A patient listing of whether or not all inclusion and exclusion criteria were met and if not, 
which criteria were not met, by patient, will also be presented. 
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10.2 
Protocol Violations or Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or Good Clinical 
Practice (GCP). The noncompliance may be either on the part of the patient, the investigator, 
or the study site staff. Since capturing every specific protocol deviation is not part of the 
eCRF database, but they will be identified and documented by Tolero Pharmaceuticals study 
monitors/project manager prior to database lock.  
All protocol deviations will be detailed in patient listings and discussed in the clinical study 
report.  
10.3 
Demographics  
Demographic characteristics will include age, gender, race, and ethnicity.  
All demographic data will be listed by patient.  
10.4 
Baseline Characteristics  
Baseline characteristics of initial diagnosis / current disesase status will include (but not 
limited to) baseline weight, height, body mass index (BMI), ECOG performance status, time 
from initial diagnosis to baseline (months), CLL/SLL type, CLL RAI stage, SLL Lugano 
stage, disease bulk, group, at high risk for Tumor Lysis Syndrome. 
Baseline characteristics of symptoms suggestive of active disease will include (but not 
limited to: XQLQWHQWLRQDOZHLJKWORVVZLWKLQWKHSUHYLRXVPRQWKV, unintentional 
ZHLJKWORVVsince last SSAD assessment, marked fatigue, fevHUV)RU&
IRUZHHNVZLWKRXWHYLGHQFHRILQIHFWLRQ, QLJKWVZHDWVIRUPRQWKZLWKRXWHYLGHQFHRI
infection 
All baseline characteristics data will be listed by patient. Medical history and pregnancy tests 
will also be listed.  
10.5 
Past Medical Therapies / Surgeries for Cancer Related Indications 
All past medical therapies and surgeries for cancer will also be listed by patient.  
10.6 
Concomitant Medications 
Concomitant and prior medications will be presented in patient listings.  
10.7 
Study Drug Administration and Exposure 
Study drug administration will be presented in patient listings. From the patient listings, the 
following information can be summarized in the clinical study report: 
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B 
3ODWHOHWFRXQW 
O 
ORU
LQFUHDVHRYHU
EDVHOLQH 
'HFUHDVHRI
fURPEDVHOLQH
VHFRQGDU\WR&// 
&KDQJHRI–WR
 
+HPRJORELQ 
JGO 
XQWUDQVIXVHG
DQGZLWKRXW
HU\WKURSRLHWLQ 
JGORU 
LQFUHDVHRYHU
EDVHOLQH 
'HFUHDVHRI JGO
IURPEDVHOLQH
VHFRQGDU\WR&// 
,QFUHDVH JGO
RURYHU
EDVHOLQHRU 
GHFUHDVH JGO 
0DUURZ 
1RUPRFHOOXODU
QR&//FHOOV
no B-O\PSKRLG
QRGXOHV 
3UHVHQFHRI&//
FHOOVRURI
B-O\PSKRLGQRGXOHV
RUQRWGRQH 
,QFUHDVHRI&// 
FHOOVE\RQ
VXFFHVVLYHELRSVLHV 
1RFKDQJHLQ
PDUURZLQILOWUDWH 
If there are items not outlined above, further detail and clarification can be obtained from the 
referenced Blood journal article authored by Hallek et al. 
The best objective response rate (CR, PR, SD, PD, NE) by the investigator-based assessment 
is defined as the percent of patients with a “best overall response” of CR or PR according to 
2018 IWCLL criterion over the time point assessments.  
The Overall Response EDC Form (dataset OR, variable name ORRESP) stores the objective 
response assessed by the investiagator based on 2018 IWCLL criteria for each patient at each 
study visit. These data be presented in the individual patient listings and swimmers plot.  
11.2 
Secondary Endpoints  
Secondary endpoints will not be analyzed via statistical methods due to low enrollment 
in Phase 1 and no enrollment in Phase 2.    
Duration of Response (DOR) will only include patients with CR or PR and is defined as the 
number of days from the initial documentation of an objective response to the most current 
evaluation of that response or to documentation of progression or death. Patients who had an 
initial response and did not progress will be censored at their date of last assessment.  
Patient listings and swimmmers plot will be used to display DoR.  
Progresson Free Survival (PFS) is defined as the time from first dose until objective tumor 
progression or death. Patient listings and swimmmers plot will be used to display the 
progression times.  
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Overall Survival (OS) is defined as the duration between the date of treatment initiation 
(Study Day 1) to the date of death, regardless of the cause of death. Patient listings will be 
used to display survival times.  
12. 
SAFETY ANALYSIS  
Safety will be evaluated from adverse events (including serious AEs and/or deaths), 
laboratory results, vital signs, physical examination, study drug exposure, and concomitant 
medications. 
The Safety Population is defined as all enrolled patients who received any amount of study 
treatment will be utilized for all safety displays.  
The safety data will be presented in the individual patient listings and patient profiles only.  
12.1 
Treatment Emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) are defined as all AEs that begin on or after the 
date of the first administration of study drug. Related AEs are those reported as possibly 
related, probably related, or related to TP-0903. The verbatim terms of the Treatment 
Emergent Adverse Events (TEAE) will be coded to preferred terms (PT) and system organ 
classes (SOC) per MedDRA® (Medical Dictionary for Regulatory Activities) Version 21.0 
(or later). 
All reported AEs (including non-TEAEs) will be listed, documenting all information 
collected on the eCRF including verbatim term, MedDRA preferred term, MedDRA system 
organ class, start date, stop date, severity and relationship to TP-0903, action taken, and 
outcome.  
The TEAEs will be graded by the Investigator in terms of: 
x Severity graded 1-5 according to CTCAE v5.0: 
o 1=Mild, 2=Moderate, 3=Severe, 4= Life Threatening, 5=Fatal. 
x Relation to TP-0903: 
o ‘Related’ includes events where the causality was reported as ‘Possibly Related’, 
or ‘Probably Related’, or ‘Definitely Related’, or where the relationship was not 
reported on the eCRF.  
o ‘Not Related’ includes events where the study drug causality was reported as 
‘Unrelated ‘or ‘Unlikely Related’ on the eCRF. 
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Patient listings will be provided to display all TEAEs reported by the three patients enrolled 
in this study.  
12.2 
Serious Adverse Events 
A listing of patients who reported a serious adverse event will be presented in a patient 
listing. The data will be obtained from the AE dataset where any of the Seriousness Criteria 
of 1-6 is checked (note: AESAE criteria 7 = NOT serious). 
12.3 
Adverse Events Leading to Discontinuation from Study 
A listing of patients and the adverse events which led to study discontinuation from the study 
will be included.  The specific AE will be identified from the AE dataset under Action Taken 
(AEACT)=8: Discontinued from Study due to this AE.    
12.4 
Deaths Due to Adverse Event 
A listing of patients who died on study will be included. The specific AE leading to death 
will be identified from the AE dataset where Outcome (AEOUT)= 5: Death related due to 
this AE or Severity (AESEV)=5: Fatal/Grade 5.   
12.5 
Dose Limiting Toxicity (DLT) and Maximum Tolerate Dose (MTD) 
All DLTs will be listed by dose cohort and patient. The MTD will be identified. The specific 
DLT will be identified from the AE dataset: AEDLT=Yes.  
12.6 
Clinical Laboratory Tests 
Safety laboratory assessments will be conducted on as specified in Schedule of Assessments 
(Section 18). 
All laboratory tests (hematology, clinical chemistry, urinalysis, coagulation, 
immunoglobulin, TS labs) values, units, normal ranges, flags collected in the clinical 
database (i.e., results that are outside the normal ranges will be flagged with “L” (below 
normal range) or “H” (above normal range)) will be included in by-patient listings for further 
medical review. 
12.6.1 Hematology 
Hematology laboratory tests are planned to include: WBC, RBC, Hemoglobin, Hematocrit, 
MCV, Platelet Count, % Neutrophils, % Lymphocyte, % Monocytes, % Eosinophils, % 
Basophils, Absolute Neutrophils, Absolute Lymphocytes, Absolute Monocytes, Absolute 
Eosinophils, Absolute Basophils.  
All Hematology test results will be presented in the patient listings. 
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12.6.2 Chemistry 
Chemistry laboratory tests are planned to include: Sodium, Potassium, Chloride, Bicarbonate 
(CO2), Calcium, Glucose, Blood Urea Nitrogen (BUN), Creatinine, Total Protein, Albumin, 
Total Bilirubin, Alkaline Phosphatase, AST / SGOT, ALT / SGPT, Lactate Dehydrogenase 
(LDH), Magnesium, Uric Acid, Phosphorus. 
All Chemistry test results will be presented in the patient listings. 
12.6.3 Coagulation 
Coagulation laboratory test are planned to include: PT and aPTT.  
All Coagulation test results will be presented in the patient listings. 
12.6.4 Urinalysis 
All Urinalysis test results will be presented in the patient listings. 
12.6.5 Immunoglobulin 
Immunoglobulin laboratory tests are planned to include: 'LUHFW$QWLJOREXOLQ6HUXPȕ-
microglobulin, Serum IgA, Serum IgG, Serum IgM, Serum IgE, and Serum IgD. 
All Immunoglobulin test results will be presented in the patient listings. 
12.6.6 TS Labs (only if subject is indicated as at high-risk for TLS) 
TS labs are planned to include: Uric Acid, Phosphate, Potassium, Calcium, Creatinine. 
 
All TS Lab test results will be presented in the patient listings. 
12.7 
Vital Signs and Weight 
Vital signs will be conducted on as specified in Schedule of Assessments (Section 18): 
Vital sign parameters to be assessed include:  
x Blood pressure (systolic and diastolic [mmHg]); 
x Heart rate (beats per minute [bpm]); 
x Respiratory rate (bpm) 
x THPSHUDWXUH) 
x Weight (lbs). 
All vital sign tests will be included in patient listings for further medical review. 
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12.8 
12-Lead Electrocardiogram (ECG)  
The ECG parameters (PR interval, QRS duration, QT, QTc, and QTcF) will be summarized 
descriptively (n, mean, SD, median, range) by group and dose cohort at each time point for 
both the observed values and the change from baseline values.  
12-lead ECG will be performed on Day 1 of each cycle prior to dosing. 
All ECG test results will be included in patient listings for further medical review. 
12.9 
ECOG Performance Status 
ECOG performance status will be assessed at Screening, and Day 1 of Cycle 1, 2, 3+, etc., 
and end of study (EOS). The ECOG performance status categories (6-point scale): 
0 - Fully active, able to carry on 3 all pre-disease performance without restriction. 
1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work. 
2 - Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 – Dead. 
All ECOG scores will be included in patient listings for further medical review. 
12.10 Physical Examination and Pregnancy Test 
Complete physical examination will be conducted on as specified in the Schedule of 
Assessments (Section 18). The complete physical examination will include dermatological, 
HEENT, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, 
musculoskeletal, neurologic, psychiatric, other. A determination of normal, abnormal, not 
done will be made for each body system examination. All Physical Examination findings will 
be presented in individual patient listings for further medical review. 
Significant findings made after the start of study medication which meet the definition of an 
AE will be recorded on the AE eCRF. 
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15. 
COMMITMENT TO GOOD STATISTICAL PRACTICE 
15.1 
Definition of Good Statistical Practice 
International Conference on Harmonisation (ICH) Guidance on Statistical Principles for 
Clinical Trials (ICH E9) implicitly defines good statistical practice. Good statistical practice 
includes both appropriate statistical designs to minimize bias and to maximize precision of 
analysis plus operational excellence to assure credibility of results. The scientific design 
associated with any clinical trial is found in the protocol and in a more detailed pre-specified 
statistical analysis plan such as this one. 
NOTE: For this study, since only three pateints enrolled at the time of study enrollment 
termination, patient listings and patient profiles will be utilized to present the data.  
15.2 
Data Management and Use of CDISC Standards 
Data standards for clinical development of drugs have been defined and are maturing under 
various initiatives through the Clinical Data Interchange Standards Consortium (CDISC). 
Tolero Pharmaceuticals will use third party vendors for clinical data collection and data 
analysis. Clinical data will be managed by Vantage Data Designs (US based CRO). and will 
be captured in electronic case report form (eCRF) by the Medrio EDC platform. The “raw” 
data contained in the eCRF clinical database will then be converted into Study Data 
Tabulation Model (SDTM) datasets per CDISC standards. The SDTM datasets will be 
utilized in creating the patient lisitngs and patient profiles. These CDISC data conversions 
will be conducted by Vantage Data Designs.  
Other applicable standards include regulatory guidance’s from the Food and Drug 
Administration (FDA), ICH Guidance on the Structure and Content of Clinical Study Reports 
(ICH E3), and ICH Guidance for Good Clinical Practice (ICH E6). 
15.3 
Testing/Validation Plan and Software System 
Statistical Analysis Software (SAS) version 9.4 or later will be used to create thepatient data 
listings and patient profiles. All SAS computer programs will be validated using industry 
standard validation procedures including independent quality control programming. 
16. 
STATISTICAL ANALYSIS CHANGES FROM THE PROTOCOL 
The analyses described are based on the final clinical study protocol TP-0903-102 
Amendment 2 dated November 13, 2018. This SAP supersedes the statistical 
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considerations identified in the protocol. A summarization of this study and the effects 
on this SAP is described below:  
On January 14, 2020 the investigative sites were notified of the decision by Tolero 
Pharmacetucial to close this study due to lack of accrual. This SAP will reflect the latest 
protocol (Amendment 2) language along with the current status where appropriate.  
Enrollment status as of January 14, 2020: 
x Phase 1: Three patients enrolled. 
 Group 1: one patient enrolled at the TP-0903 25 mg flat dose. 
 Group 2: two patients enrolled. Both were at the TP-0903 20 mg 
flat dose group in combination with ibrutinib at the same dose that 
they were receiving immediately prior to study enrollment.  
x Phase 2: no patients enrolled 
This study terminated enrollment before MTD and RP2D was identified.  
Effiacy endpoints will not be analyzed via statistical methods due to low enrollment in 
Phase 1 and no enrollment in Phase 2. Patient listings, patient profiles, and swimmers 
plot will be used to display the efficacy data.  
Safety data will be displayed using only the patient listings and patient profiles.  
17. 
REFERENCES 
1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. 
Guidelines for Diagnosis, Indications for Treatment, Response Assessment and 
Supportive Management of Chronic Lymphocytic Leukemia (An Update of the NCI-
sponsored guidelines from the International Workshop on Chronic Lymphocytic 
Leukemia). Prepublished online March 14, 2018; doi:10.1182/blood-2017-09-806398. 
Available from: http://www.bloodjournal.org/content/early/2018/03/14/blood-2017-09-
806398. 
2. FDA Draft Guidance for Industry: Clinical Trial Imaging Endpoint Process Standards. 
March 2015. 
3. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
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4. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Good Clinical 
Practice: Consolidated Guidance (E6), April 1996. 
5. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical 
Principles for Clinical Trials (E9), 5 February 1998. 
6. International Federation of Pharmaceutical Manufacturers and Associations. Medical 
Dictionary for Regulatory Activities (MedDRA). Version 21.0.  Reston, Virginia, USA; 
2008. 
7. Protocol TP-0903-102: A Combined Phase 1/2 Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity of TP-0903 in Patients with 
Previously Treated Chronic Lymphocytic Leukemia (CLL). Amendment 2, November 
13, 2018. 
8. SAS Institute Inc. SAS Version 9.4. Cary, NC, USA; 2002-2003. 
9. Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials; Controlled Clinical 
Trials 1989;10(1):1–10.  
10. WHO Collaborating Center for International Drug Monitoring. WHO Drug Dictionary. 
June 2018 B2 Enhanced edition. Uppsala, Sweden; 2008.
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r 
Collect blood for PD PBMCs, plasma and serum at C1D1 pre-dose, 2 hr, 6 hr and 24 hr postdose (predose C1D2), C1D8 predose and Day 1 
of every cycle and EOS 
s 
PK samples will be collected only in the Phase 1 portion of the study, on Days 1 and 28 of Cycle 1 just before dosing and at 1, 2, 6, and 
24 hours postdose (prior to the next daily dose of TP-0903) and on Day 1 of each subsequent cycle. PK samples should be collected on 
protocol-specified days, regardless of visit windows. 
t 
Study drug should be taken in the morning after an overnight fast with up to 200 mL or 7 fluid ounces of water at least 1 hour before ingesting 
any food or other medications. For patients in Group 2, ibrutinib should be taken as directed and per the approved label instructions. 
u 
Patients will be given a Patient Dosing Diary (Appendix I) in which to record the date, time, number of capsules taken, whether a dose was 
missed, or if patient vomited for both TP-0903 and ibrutinib. Patients will be instructed to bring their diary and all study drug bottles to each 
follow-up clinic visit so that the diary can be reviewed by study personnel and a capsule count performed to ensure dosing compliance. 
v 
Collect bone marrow at CR for determination of MRD (central lab assessment)  
w 
Long-term follow up for survival 2 years: Year 1- monthly contacts (±7 days) starting 1 month after completion of EOS; Year 2- contacts every 
other month for the following: date of death, date of relapse, or continued remission 
x   PET scan to rule out Richter’s Transformation to be completed within 14 days of first dose 
y 
TLS labs to be assessed at baseline (predose) and at 6 hours and 24 hours post dose (real-time [STAT] review) in patients at high risk for TLS 
(ie, SDWLHQWVZLWKDQ\/1FPRU$/& × 109/DQGDQ\/1 cm) 
 
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