A Phase 3 Open-Label, Randomized Study of LOXO-305 Versus Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321)
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Sponsor: Loxo Oncology, Inc.

Protocol LOXO-BTK-20020 (J2N-OX-JZNN) Version 6.2
Study of LOXO-305 Versus Investigator's Choice (IdelaR or BR) in Patients With Previously 
Treated Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) (BRUIN 
CLL-321)
NCT04666038
Approval Date: 14-Jun-2024

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 1 of 181 
CLINICAL PROTOCOL LOXO-BTK-20020 
A Phase 3 Open-Label, Randomized Study of LOXO-305 versus 
Investigator’s Choice of Idelalisib plus Rituximab or 
Bendamustine plus Rituximab in BTK Inhibitor Pretreated 
Chronic Lymphocytic Leukemia/Small Lymphocytic 
Lymphoma (BRUIN-CLL-321) 
Investigational Product: 
Pirtobrutinib (LOXO-305, LY3527727) 
Protocol Number: 
LOXO-BTK-20020 (J2N-OX-JZNN) 
Development Phase: 
3 
IND #: 
139876 
EudraCT#: 
2020-004554-30 
EU Trial #: 
2023-507697-40-00 
Sponsor: 
Loxo Oncology, Inc. 
281 Tresser Boulevard 
Stamford, CT 06901 
Version: 
6.2 
Date: 
14 June 2024 
Confidentiality Statement 
This document contains confidential information that is the property of Loxo Oncology Inc. 
(Loxo) and/or Eli Lilly and Company (Lilly) and may not be disclosed to anyone other than the 
recipient Clinical Investigator, research staff, and respective members of the Institutional Review 
Board/Independent Ethics Committee. This information cannot be used for any purpose other 
than the evaluation of conduct of the clinical investigation without the prior written consent of 
Loxo and/or Lilly. 
Note to Regulatory Authorities: 
This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure. Loxo and/or Lilly requests consultation regarding 
release/redaction prior to any public release. In the United States, this document is subject to 
Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise 
disseminated without the written approval of Loxo and/or Lilly.

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 2 of 181 
PROTOCOL APPROVAL PAGE 
Protocol Title: 
A Phase 3 Open-Label, Randomized Study of 
LOXO-305 versus Investigator’s Choice of 
Idelalisib plus Rituximab or Bendamustine plus 
Rituximab in BTK Inhibitor Pretreated Chronic 
Lymphocytic Leukemia/Small Lymphocytic 
Lymphoma (BRUIN-CLL-321) 
Protocol Number: 
LOXO-BTK-20020 (J2N-OX-JZNN) 
Version: 
6.2 
Date: 
14 June 2024 
The current version of the protocol has been reviewed and approved. 
e-signature can be found at the end of this document
____________________________________
_______________ 
Date 
I have carefully read Protocol LOXO-BTK-20020 entitled “A Phase 3 Open-Label, Randomized 
Study of LOXO-305 versus Investigator’s Choice of Idelalisib plus Rituximab or Bendamustine 
plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic 
Lymphoma (BRUIN-CLL-321).” I confirm that I have read and agree to conduct the clinical 
study as outlined in the protocol and in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki as amended, and all other applicable regulatory requirements. 
Furthermore, I understand that the Sponsor, Loxo Oncology Inc., and the Institutional Review 
Board/Research Ethics Board/Independent Ethics Committee (IRB/REB/IEC) must approve 
any changes to the protocol in writing before implementation. 
I agree on behalf of myself and all other personnel involved in the clinical study who are 
employed by me, to maintain confidentiality of all information received or developed in 
connection with this protocol. All data pertaining to this study will be provided to 
Loxo Oncology and/or Eli Lilly and Company (Lilly) and any presentation or publication of 
study data will be reviewed by Loxo Oncology and/or Lilly before release. 
____________________________________ 
_______________ 
Principal Investigator’s Signature  
Date 
___________________________________ 
Print Principal Investigator’s Name 
PPD

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 3 of 181 
PROTOCOL VERSION HISTORY 
Document 
Date 
Version 6.2 
14 June 2024 
Version 6.1 (EU) 
12 March 2024 
Version 6.0 
15 February 2023 
Version 5.0 
13 September 2022 
Version 4.0 
06 August 2021 
Version 3.0 
07 December 2020 
Version 2.0 
03 November 2020 
Version 1.0 
13 October 2020 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 4 of 181 
TABLE OF CONTENTS 
 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
PROTOCOL VERSION HISTORY ............................................................................................3 
Table of Contents ...........................................................................................................................4 
List of Tables ..................................................................................................................................8 
1. 
Protocol Summary .............................................................................................................9 
1.1. 
Synopsis ...................................................................................................................9 
1.2. 
Schema ...................................................................................................................14 
1.2.1. Study Design Schema ................................................................................14 
1.2.2. Schema for 17p Deletion Stratification......................................................15 
1.3. 
Schedule of Assessments .......................................................................................16 
1.3.1. Schedule of Assessments for Arm A: Pirtobrutinib 
Monotherapy ..............................................................................................17 
1.3.2. Schedule of Assessments for Arm B: Idelalisib plus 
Rituximab ...................................................................................................26 
1.3.3. Schedule of Assessments for Arm B: Bendamustine 
plus Rituximab ...........................................................................................37 
1.3.4. Schedule of Assessments for Optional Crossover 
Treatment (for Patients Crossing Over from Arm B 
to Arm A) ...................................................................................................46 
1.3.5. Schedule of Assessments for Response 
Assessments, Arms A and B (Does not Apply for 
Crossover) ..................................................................................................51 
1.3.6. Schedule of Assessments for Patient-Reported 
Outcomes, Arms A and B ..........................................................................53 
2. 
Introduction ......................................................................................................................54 
2.1. 
Study Rationale ......................................................................................................54 
2.2. 
Background ............................................................................................................54 
2.2.1. Current Approaches to Treatment of CLL/SLL.........................................56 
2.3. 
Benefit/Risk Assessment .......................................................................................58 
3. 
Objectives and Endpoints................................................................................................61 
4. 
Study Design .....................................................................................................................62 
4.1. 
Overall Design .......................................................................................................62 
4.2. 
Scientific Rationale for Study Design....................................................................62 
4.3. 
Justification for Dose .............................................................................................62 
4.3.1. Pirtobrutinib ...............................................................................................62 
4.3.2. Idelalisib plus Rituximab ...........................................................................63 
4.3.3. Bendamustine plus Rituximab ...................................................................63 
4.4. 
End of Study Definition .........................................................................................64 
5. 
Study Population ..............................................................................................................65 
5.1. 
Inclusion Criteria ...................................................................................................65 
5.2. 
Exclusion Criteria ..................................................................................................68 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 5 of 181 
5.3. 
Eligibility Criteria for Crossover Treatment ..........................................................71 
5.4. 
Lifestyle Considerations ........................................................................................72 
5.4.1. Meals and Dietary Restrictions ..................................................................72 
5.5. 
Screen Failures .......................................................................................................72 
6. 
Study Intervention ...........................................................................................................73 
6.1. 
Study Interventions Administered .........................................................................73 
6.1.1. Selection and Timing of Doses ..................................................................73 
6.1.2. Arm A Pirtobrutinib: General Dosing Instructions ....................................74 
6.1.3. Arm B Investigator’s Choice of IdelaR or BR: 
General Dosing Instructions ......................................................................74 
6.2. 
Preparation/Handling/Storage/Accountability .......................................................76 
6.2.1. Arm A Preparation/Handling/Storage: Pirtobrutinib .................................76 
6.2.2. Arm B Preparation/Handling/Storage: Investigator’s 
Choice of IdelaR or BR..............................................................................76 
6.3. 
Measures to Minimize Bias: Randomization .........................................................76 
6.4. 
Study Intervention Compliance .............................................................................77 
6.5. 
Concomitant Therapy.............................................................................................77 
6.5.1. Allowed Concomitant Medication and Supportive 
Care ............................................................................................................77 
6.5.2. Prohibited Concomitant Medication ..........................................................79 
6.5.3. Subsequent Anticancer Therapy ................................................................79 
6.6. 
Dose Modification Guidelines ...............................................................................80 
6.6.1. Dose Modifications and Toxicity Management 
Guidelines for Arm A: Pirtobrutinib ..........................................................81 
6.6.2. Dose Modification and Toxicity Management 
Guidelines for Arm B: Idelalisib, Rituximab, 
Bendamustine .............................................................................................82 
6.7. 
Intervention after the End of the Study ..................................................................85 
6.7.1. Treatment after Study Completion.............................................................85 
6.7.2. Crossover to Pirtobrutinib ..........................................................................86 
6.7.3. End of Treatment .......................................................................................87 
6.7.4. Safety Follow-up ........................................................................................87 
6.7.5. Long-Term Follow-up ...............................................................................87 
7. 
Discontinuation of Study Intervention and Patient 
Discontinuation/Withdrawal ...........................................................................................89 
7.1. 
Discontinuation of Study Intervention ...................................................................89 
7.2. 
Patient Discontinuation/Withdrawal from the Study .............................................90 
7.2.1. Discontinuation of Inadvertently Enrolled Patients ...................................90 
7.3. 
Lost to Follow-up ...................................................................................................90 
8. 
Study Assessments and Procedures ................................................................................91 
8.1. 
Screening................................................................................................................91 
8.2. 
Medical History .....................................................................................................91 
8.3. 
Efficacy Assessments.............................................................................................91 
8.3.1. Response Assessment ................................................................................91 
8.3.2. IRC Assessment .........................................................................................93 
8.4. 
Safety Assessments ................................................................................................93 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 6 of 181 
8.4.1. Vital Signs ..................................................................................................93 
8.4.2. Physical Examination.................................................................................93 
8.4.3. Electrocardiograms ....................................................................................93 
8.4.4. Clinical Safety Laboratory Assessments ...................................................94 
8.5. 
Adverse Events and Serious Adverse Events and Other 
Safety Reporting ....................................................................................................98 
8.5.1. Definitions..................................................................................................98 
8.5.2. Grading and Intensity of Adverse Events ..................................................99 
8.5.3. Relationship to Underlying Disease, Other Medical 
Condition or Concomitant Medications ...................................................100 
8.5.4. Adverse Event Reporting .........................................................................100 
8.5.5. Serious Adverse Event Reporting ............................................................100 
8.5.6. Serious Adverse Event Follow-up ...........................................................101 
8.5.7. Pregnancy Reporting ................................................................................101 
8.5.8. Second Primary Malignancy Reporting ...................................................102 
8.6. 
Treatment of Overdose ........................................................................................102 
8.7. 
Pharmacokinetics .................................................................................................102 
 
 ..............................................................................................102 
8.9. 
Genetics................................................................................................................103 
8.9.1. Bone Marrow 
 Biopsy ..........................................................103 
8.9.2. Pathology and Molecular Reports ............................................................103 
 
 ...........................................................................................................103 
 
 ...................................................................................103 
 ......................................................104 
8.11. Immunogenicity Assessments ..............................................................................104 
8.12. Medical Resource Utilization and Health Economics .........................................104 
8.12.1. Patient-Reported Outcomes .....................................................................104 
8.12.2. Medical Resource Utilization ..................................................................106 
9. 
Statistical Considerations ..............................................................................................107 
9.1. 
Statistical Hypotheses ..........................................................................................107 
9.2. 
Sample Size Determination..................................................................................107 
9.3. 
Populations for Analyses .....................................................................................107 
9.4. 
Statistical Analyses ..............................................................................................107 
9.4.1. General Statistical Considerations ...........................................................107 
9.4.2. Study Endpoints .......................................................................................108 
9.4.3. Treatment Group Comparability ..............................................................108 
9.4.4. Efficacy Analyses ....................................................................................108 
9.4.5. Safety Analyses ........................................................................................110 
9.4.6. Pharmacokinetic/Pharmacodynamic Analyses ........................................110 
9.4.7. Other Analyses .........................................................................................110 
9.5. 
Interim Analyses ..................................................................................................111 
9.6. 
Data Monitoring Committee ................................................................................111 
10. 
Supporting Documentation and Operational Considerations ...................................112 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations......................................................................................................112 
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 7 of 181 
10.1.1. Regulatory and Ethical Considerations ....................................................112 
10.1.2. Informed Consent Process .......................................................................112 
10.1.3. Serious Adverse Event Notification to the 
Institutional Review Board/Independent Ethics 
Committee ................................................................................................113 
10.1.4. Sponsor Safety Reporting to Regulatory Authorities ..............................113 
10.1.5. Data Protection.........................................................................................113 
10.1.6. Independent Review Committee Structure ..............................................114 
10.1.7. Dissemination of Clinical Study Data......................................................114 
10.1.8. Data Quality Assurance ...........................................................................114 
10.1.9. Data Capture System................................................................................115 
10.1.10. Source Documents ..............................................................................116 
10.1.11. Study and Site Closure ........................................................................116 
10.2. Appendix 2: Contraceptive Guidance and Pregnancy 
Information ..........................................................................................................117 
10.3. Appendix 3: Liver Safety .....................................................................................119 
10.4. Appendix 4: Restricted and Prohibited Concomitant 
Medication ...........................................................................................................120 
10.5. Appendix 5: Creatinine Clearance Formula ........................................................123 
10.6. Appendix 6: iwCLL 2018 Response Criteria.......................................................124 
10.7. Appendix 7: QTcF Measurement Adjustment in Patients 
with a Widened QRS Complex > 110 ms ............................................................125 
10.8. Appendix 8: Abbreviations and Definitions ........................................................126 
10.9. Appendix 9: Country-Specific Requirements ......................................................132 
10.9.1. Belgium ....................................................................................................132 
10.9.2. Czech Republic ........................................................................................134 
10.9.3. Germany ...................................................................................................151 
10.9.4. France .......................................................................................................166 
10.10. Appendix 10: Exceptional Circumstances: Provisions for 
Changes in Study Conduct During Exceptional 
Circumstances ......................................................................................................172 
10.10.1. Purpose for Appendix .........................................................................172 
10.10.2. Specific Changes to this Protocol .......................................................173 
10.10.3. Documentation ....................................................................................174 
10.10.4. Tabular Summary of Changes in this Appendix .................................175 
10.10.5. Changes in Protocol Section 1.3: Schedule of 
Assessments .............................................................................................176 
11. 
References .......................................................................................................................177 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 8 of 181 
LIST OF TABLES 
Table 3.1 
Objectives and Endpoints ..................................................................................... 61 
Table 6.1 
Intervention Groups and Duration ........................................................................ 73 
Table 6.2 
Specific Instructions for Idelalisib plus Rituximab or 
Bendamustine plus Rituximab .............................................................................. 75 
Table 6.3 
Adverse Events Requiring Dose Modification for 
Pirtobrutinib .......................................................................................................... 81 
Table 6.4 
Recommended Dose Modifications for Idelalisib ................................................ 82 
Table 6.5 
Dose Modifications for Bendamustine ................................................................. 84 
Table 9.1 
Analysis Populations ........................................................................................... 107 
Table 10.1 
Inhibitors of CYP3A4 ......................................................................................... 120 
Table 10.2 
Inducers of CYP3A4 ........................................................................................... 121 
Table 10.3 
CYP3A Sensitive Substrates ............................................................................... 121 
Table 10.4 
P-gp Substrates.................................................................................................... 122 
Table 10.5 
CYP2C8 Substrates ............................................................................................. 122 
Table 10.6  
BCRP Substrates ................................................................................................. 122 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 9 of 181 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A Phase 3 Open-Label, Randomized Study of LOXO-305 versus Investigator’s Choice of 
Idelalisib plus Rituximab or Bendamustine plus Rituximab in BTK Inhibitor Pretreated Chronic 
Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN-CLL-321) 
Short Title:  
A Phase 3 Study Comparing LOXO-305 to Investigator’s Choice of Idelalisib plus Rituximab or 
Bendamustine plus Rituximab 
Regulatory Agency Identifier Number: 
EudraCT#: 
2020-004554-30 
EU Trial #: 
2023-507697-40-00 
Rationale:  
The treatment landscape for patients with chronic lymphocytic leukemia (CLL)/small 
lymphocytic lymphoma (SLL) has changed radically over the last 10 years, resulting in markedly 
improved long-term outcomes (Burger 2020). While chemoimmunotherapy combined with an 
anti-CD20 antibody had previously formed the foundation of therapy, more recent insights into 
the biologic dependence of CLL/SLL on B-cell receptor signaling as well as anti-apoptotic 
machinery has led to the successful development of several novel targeted therapies including 
agents inhibiting the Bruton’s tyrosine kinase (BTK), B-cell lymphoma 2 (BCL2), and 
phosphoinositide 3-kinase (PI3K) delta. The introduction of these novel agents, in particular the 
covalent BTK inhibitors (ibrutinib and acalabrutinib) and the BCL2 inhibitor venetoclax, have 
substantially improved the outcome of patients with CLL and have likewise become mainstays 
of initial therapy for treatment-naïve patients (Fischer et al. 2019; Shanafelt et al. 2019; 
Woyach et al. 2018; Burger et al. 2015). 
For patients who have previously received a covalent BTK inhibitor, therapeutic options include 
a venetoclax-based regimen (Seymour et al. 2018), a PI3K inhibitor (idelalisib or duvalesib 
depending on region) with or without rituximab (Furman et al. 2014; Flinn et al. 2018), 
chemoimmunotherapy (Fischer et al. 2008; Cuneo et al, 2018), or a clinical trial. Choice among 
these various options is dictated by patient characteristics, comorbid illness, CLL prognostic 
factors, clinical practice setting, patient preference, and region (Siegel et al. 2020). While a 
previous randomized study of venetoclax-containing therapy in BTK-naïve, relapsed CLL/SLL 
demonstrated significant improvement in outcomes, not all patients are able to receive 
venetoclax due to comorbid illness or logistical barrier (Seymour et al. 2018, Fischer et al. 2019). 
Key challenges associated with venetoclax include the risk of myelosuppression (especially in 
patients who received prior chemoimmunotherapy), risk of tumor lysis syndrome and its 
consequences including renal failure, and the need for intense monitoring and sometimes 
hospitalization to administer this oral regimen, which collectively can be prohibitive for some 
patients.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 10 of 181 
For patients previously treated with covalent BTK inhibitors and/or venetoclax, remaining 
available treatment options include chemoimmunotherapy and PI3K inhibitors. Of note, while 
these agents are widely employed in this setting, the true efficacy and safety of 
chemoimmunotherapy and PI3K inhibitors following exposure to either covalent BTK inhibitors 
or venetoclax is not well established and has not been subjected to prospective clinical studies. 
As such, protocol LOXO-BTK-20020 will not only establish the potential role for pirtobrutinib 
(LOXO-305) in patients previously treated with at least a covalent BTK inhibitor, but also help 
establish the efficacy of the control arm (Investigator’s Choice of bendamustine plus rituximab 
[BR] or idelalisib plus rituximab [IdelaR]) in this patient population. 
Pirtobrutinib: 
Pirtobrutinib is an orally available, highly selective, adenosine triphosphate (ATP)-competitive 
inhibitor of BTK. Pirtobrutinib has single digit nanomolar inhibitory activity against wildtype 
BTK and the BTK C481S acquired resistance mutation which results from a serine substitution 
at position 481. 
Pirtobrutinib is distinct from the approved BTK inhibitors (ibrutinib, approved globally for 
CLL/SLL and mantle cell lymphoma [MCL]; acalabrutinib, approved in select countries for 
CLL/SLL and MCL; zanubrutinib, approved in the United States [US] for MCL) on the basis 
of its selectivity, pharmacologic and pharmacokinetic (PK) properties, and non-covalent binding 
mode (Brandhuber et al. 2018). These features enable pirtobrutinib to achieve PK exposures with 
once daily oral dosing that exceed the BTK-wild type 90% inhibitory concentration (IC90) at 
trough and thus deliver tonic BTK target inhibition throughout the dosing period, regardless of 
the intrinsic rate of BTK turnover. Moreover, the non-covalent binding mode of pirtobrutinib is 
unaffected by BTK cysteine residue at position 481 (C481) substitutions, a common mechanism 
of drug resistance described for all available covalent inhibitors. (Byrd et al. 2013; 
Woyach et al. 2017; Woyach et al. 2019; Chiron et al. 2014; Xu et al. 2017). Finally, 
pirtobrutinib is also a highly selective molecule, with more than 300-fold more selectivity for 
BTK versus 370 other kinases tested and no significant inhibition of non-kinase off-targets at 
1 µM, thus limiting the potential for off-target mediated toxicities. 
Study results from a 
 study 
 evaluating the 
 
 of pirtobrutinib showed that 
 
 
 
In a Phase 1/2 study (LOXO-BTK-18001, NCT03740529), pirtobrutinib has demonstrated robust 
and durable antitumor activity against a variety of B-cell malignancies including CLL/SLL, 
regardless of prior treatment, including in patients treated with covalent BTK inhibitors. Of note, 
this promising activity in CLL/SLL patients has been observed in patients with both wildtype 
BTK as well as those harboring BTK C481 mutations (Mato et al. 2021).  
The purpose of this global study is to compare the efficacy and safety of pirtobrutinib 
administered as a continuous monotherapy versus Investigator’s choice of 2 globally approved 
standards of care, idelalisib with rituximab (IdelaR) or bendamustine with rituximab (BR), 
in patients with previously treated CLL/SLL including for patients with 17p deletion (del 17p) 
who have received at least one prior regimen, including a BTK inhibitor. 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 11 of 181 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate progression-free survival 
(PFS) of pirtobrutinib as monotherapy 
(Arm A) compared to Investigator’s 
choice of idelalisib plus rituximab 
(IdelaR) or bendamustine plus 
rituximab (BR) (Arm B). 
Assessed by Independent Review Committee (IRC): 
• PFS per International Workshop on Chronic Lymphocytic 
Leukemia (iwCLL 2018) 
Secondary 
• To evaluate the effectiveness of Arm 
A compared to Arm B based on 
overall response rate (ORR) and time 
to event(s) outcomes  
• Assessed by Investigator:  
- PFS per iwCLL 2018 criteria 
- Overall survival (OS) 
- Time to next treatment (TTNT), defined as time from the date 
of randomization to the date of the next systemic anticancer 
therapy for CLL/SLL (Section 9 for full definition). 
- Event free survival (EFS) defined as the time from date of 
randomization to the date of progressive disease (PD) or start 
of new treatment for CLL/SLL or discontinuation from 
treatment due to toxicity or death, whichever occurs first. 
• Assessed by Investigator and IRC: 
- ORR 
- Duration of response (DOR) 
• To evaluate the safety and tolerability 
of each treatment arm 
• Including, but not limited to, serious adverse events (SAEs), 
adverse events (AEs), deaths and clinical laboratory abnormalities 
per National Cancer Institute Common Terminology Criteria in 
Adverse Events v5.0 (NCI CTCAE v5.0) 
• To evaluate the effectiveness of Arm 
A compared to Arm B based on 
patient-reported outcomes  
• Patient-reported outcomes of: 
- Time to worsening (TTW) of CLL/SLL-related symptoms 
- TTW of physical functioning 
Overall Design:  
LOXO-BTK-20020 (BRUIN-CLL-321) is a Phase 3 global, randomized, open-label study 
comparing pirtobrutinib as continuous monotherapy (Arm A) to Investigator’s choice of either 
IdelaR or BR (Arm B) in CLL/SLL patients who have been treated with a covalent BTK 
inhibitor, approved (ibrutinib or acalabrutinib) or investigational. Patients may have discontinued 
the prior covalent BTK due to PD or intolerance. The reason for prior discontinuation will be 
recorded. Eligible patients will be randomized in 1:1 into Arm A and Arm B based on 
stratification factors of deletion 17p presence (yes/no) and receipt of prior venetoclax treatment 
(yes/no).  
BRUIN-CLL-321 will enroll adult CLL/SLL patients with an indication for treatment as defined 
by iwCLL 2018 criteria (Hallek et al. 2018; Cheson et al. 2012; Section 10.6, Appendix 6). 
During Screening, Investigator’s choice therapy (IdelaR or BR) must be selected by the 
Investigator prior to randomization for each patient. Patients who have been previously treated 
with IdelaR or BR and had either documented PD as determined by the Investigator, or could not 
tolerate the regimen, should not be retreated with same regimen. Patients assigned to oral 
pirtobrutinib will receive pirtobrutinib continuously until discontinuation criteria are met 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 12 of 181 
(Section 7.1). Patients assigned to BR will receive up to 6 cycles of both agents intravenously 
(IV) unless they experience unacceptable toxicity or progression, at which time patients will 
discontinue treatment. Patients who complete the full course of BR will be followed until 
progression, death, lost to follow-up or withdrawal of consent. Patients will be allowed to cross 
over from Arm B to Arm A upon confirmation of PD by IRC and if they meet the eligibility 
criteria for crossover (Section 5.3). Patients who have PD per the Investigators’ assessment but 
not IRC confirmed are not eligible for crossover until they meet IRC PD criteria. Patients who 
progress on Arm A are not eligible for crossover but may be allowed to continue treatment 
beyond progression if the patient is tolerating study treatment and, in the opinion of the 
Investigator, is deriving ongoing clinical benefit. Continuation of treatment on Arm A post-
progression must be approved by the Sponsor. Patients will need to be consented for treatment 
beyond progression on pirtobrutinib. Patients who progress on Arm B and decide to continue 
treatment are no longer eligible for crossover to Arm A (patients on idelalisib may continue 
while patients are undergoing Screening for crossover, but will need to meet the criteria for 
washout duration prior to starting pirtobrutinib if they meet all other eligibility criteria). Patients 
who discontinue treatment for any reason other than PD, death, lost to follow-up, or withdrawal 
of consent will be followed for tumor assessment until PD, regardless of whether the patient 
receives a new anticancer therapy. Upon PD, all patients will then be placed on Long-Term 
Follow-up (LTFU) every 3 months until death, lost to follow-up, or consent withdrawal. 
Pirtobrutinib: Patients randomized to Arm A will receive treatment with pirtobrutinib 
monotherapy (refer to Treatment Groups). 
Investigator’s choice of idelalisib plus rituximab (IdelaR) OR bendamustine plus rituximab 
(BR): Patients randomized to Arm B will receive treatment at the dose and schedule appropriate 
for the diagnosis and according to approved prescribing instructions (refer to Treatment Groups).  
On days when rituximab and bendamustine are to be administered, rituximab will be 
administered prior to bendamustine. 
Disclosure Statement:  
This is a randomized, active treatment study with 2 arms where the patient and Investigator will 
not be blinded.  
Study Population: 
The study includes patients age 18 or older (per local regulations at time of enrollment) with 
CLL/SLL who have been treated with an approved or investigational covalent BTK inhibitor. 
Patients must have confirmed diagnosis of CLL/SLL by redacted local laboratory report as 
defined by iwCLL 2018 criteria (see Sections 1.2.1 and 5.1).  
Number of Patients: 
Approximately 250 patients will be randomized 1:1, Arm A:Arm B, based on stratification 
factors of del 17p presence (yes/no) and receipt of prior venetoclax treatment (yes/no) (see 
Sections 1.2.1 and 1.2.2). 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 13 of 181 
Treatment Groups: 
 
Arm A 
pirtobrutinib 
Arm B  
Investigator’s choice of idelalisib plus rituximab (IdelaR) or  
bendamustine plus rituximab (BR) 
idelalisib plus rituximab (IdelaR) 
bendamustine plus rituximab (BR) 
Treatment 
pirtobrutinib 
idelalisib 
rituximab 
bendamustine 
rituximab 
Dose 
200 mg 
150 mg 
375 mg/m2 on 
C1D1 and then 
500 mg/m2 
70 mg/m2  
375 mg/m2 on 
C1D1 and then 
500 mg/m2 
Schedule 
QD in 28-day 
continuous 
cycles 
BID in 28-day 
continuous 
cycles 
375 mg/m2 on 
C1D1 and then 
500 mg/m2 Q2W 
for 4 infusions 
and Q4W for 
3 infusions 
70 mg/m2 on Day 
1 and Day 2 of 
each 28-day cycle, 
Cycles 1 to 6 
375 mg/m2 on 
C1D1 and then 
500 mg/m2 
given on Day 1 
of each 28-day 
cycle, Cycles 2 
to 6 
Route 
Oral 
Oral 
IV 
IV 
IV 
Authorized as 
defined by EU 
Clinical Trial 
Regulation 
Not 
authorized in 
EU 
Authorized and 
used according to 
EU authorization 
Authorized and 
used according to 
EU authorization 
Approved in the 
EU and used 
at the dose 
recommended by 
the International 
Consensus Panel 
(see Section 4.3.3) 
Authorized and 
used according to 
EU authorization 
 
Ethical Considerations of Benefit/Risk: 
During Phase 1 and 2 studies, pirtobrutinib has demonstrated a tolerable safety profile and 
durable antitumor activity against a variety of B-cell malignancies, including pretreated 
CLL/SLL. Additionally, considering the measures taken to ensure patient safety in this study, the 
potential risks from taking the study interventions are outweighed by the potential benefits for 
individuals with CLL/SLL 
Data Monitoring Committee:  
A Data Monitoring Committee (DMC) will be utilized to review aggregate safety data for this 
study. Please refer to the DMC charter for further information. 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 14 of 181 
1.2. 
Schema 
1.2.1. 
Study Design Schema 
 
a Detailed study treatment dosing instructions are provided in Section 6.1. 
b Day 1 of Cycle 1, first dose of rituximab at 375 mg/m2, next 4 infusions at 500 mg/m2 every 
2 weeks (Q2W), next 3 infusions at 500 mg/m2 every 4 weeks (Q4W).  
c Day 1 of Cycle 1, first dose of rituximab at 375 mg/m2, next 5 infusions Day 1 of Cycle 2 
through Cycle 6 at 500 mg/m2. 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 15 of 181 
1.2.2. 
Schema for 17p Deletion Stratification 
 
a FISH results collected for del 17p will be used to stratify patients for randomization, with a sample 
collected for retrospective central confirmation. 
b Del 17p should be documented by a redacted molecular pathology report generated from a local or central 
laboratory with CLIA, ISO/IEC, CAP, or other similar certification.  
c For SLL patients, local 17p assessment on fresh lymph node biopsy is acceptable. 
d The Sponsor should be contacted to discuss test results performed in laboratories where CLIA, ISO/IEC, 
CAP, or other similar certification is not clearly demonstrated to determine if retesting should be 
performed. 
Note: 17p testing will not be repeated at the time of crossover if results were wildtype at the time of study 
entry regardless of the duration interval from study entry (i.e., > 6 months).  
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 16 of 181 
1.3. 
Schedule of Assessments 
This section includes Schedules of Assessments (SoAs) for patients receiving the following 
treatments: 
• ARM A: pirtobrutinib (Section 1.3.1)  
• ARM B: idelalisib with rituximab (IdelaR) (Section 1.3.2)  
• ARM B: bendamustine with rituximab (BR) (Section 1.3.3)  
• Optional crossover treatment (for patients crossing over from Arm B to Arm A) 
(Section 1.3.4)  
Additional SoAs include the following: 
• The Response Assessment SoA is provided in Section 1.3.5. 
• The Patient-Reported Outcomes (PRO) SoA is provided in Section 1.3.6.

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 17 of 181 
1.3.1. 
Schedule of Assessments for Arm A: Pirtobrutinib Monotherapy  
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
Informed consent 
X 
 
 
 
 
 
 
 
The ICF must be signed before any 
protocol-specified procedures are 
performed; refer to Section 10.1.2 
Medical history 
X 
 
 
 
 
 
 
 
All ongoing conditions and relevant past 
surgical and medical history should be 
collected; refer to Section 8.2 
• Malignancy history should be collected 
regarding disease under study, and any 
history of other malignancy 
• Prior therapy related to CLL/SLL would 
be collected as part of the medical 
history, including reason for prior 
covalent BTK discontinuation 
Documentation of 
diagnosis and 
relevant 
biomarkers  
X 
 
 
 
 
 
 
 
• Anonymized/redacted pathology 
report(s) confirming diagnosis of CLL 
required for eligibility 
• Reports regarding status of any known 
CLL relevant biomarkers should be 
provided if available (e.g., IGHV, TP53 
mutation, complex karyotype, del 11q, 
BTK mutation and PLCg2 mutation) 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 18 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
Physical 
examination 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter  
X 
X 
X 
• Complete PE includes height (only at 
Screening), weight, basic neurological 
examination, and review of relevant 
symptoms at Screening; refer to 
Section 8.4.2 
• Symptom-directed PE should be limited 
to systems of primary relevance such as, 
cardiovascular, respiratory, and those 
associated with tumor assessment 
(lymph nodes, liver, and spleen) and 
may be performed at other timepoints; 
include weight as clinically indicated 
throughout the trial 
• Screening results obtained within 3 days 
of C1D1 are acceptable as C1D1 results 
ECOG PS 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter 
X 
X 
 
• Includes systolic and diastolic blood 
pressure, heart rate, respiratory rate and 
body temperature 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 19 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
Results of tests in the section below are required for eligibility determination and enrollment 
Deletion 17p 
evaluation 
X 
 
 
 
 
 
 
 
• Refer to Section 1.2.2 
• Results are required for stratification 
CMV 
X 
 
 
 
 
 
 
 
CMV IgG, IgM and DNA PCR at 
Screening only (Section 8.4.4.5)` 
12-lead ECG 
X 
X 
 X 
X 
C7D1 and 
Q12W 
thereafter 
X 
 
 
• Obtain ECGs at specified visits and 
when patients are symptomatic; refer to 
Section 8.4.3 
• ECGs should be collected: 
− At Screening, single ECG  
− C1D1: Predose single ECG  
− All other timepoints: Post dose 
single ECG 
− If an unscheduled ECG is done at 
any time, an electrolyte panel (i.e., 
calcium, magnesium, and 
potassium) must be done to coincide 
with the ECG 
− If a clinically significant arrhythmia 
is detected, details must be in EDC 
Hematology 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter 
X 
X 
X 
• Includes hemoglobin, hematocrit, RBC 
count, WBC count, platelet count, 
percent or absolute differential 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 20 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
(neutrophils, lymphocytes, eosinophils, 
basophils, and monocytes) 
• Screening results obtained within 3 days 
of C1D1 are acceptable as C1D1 results 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
• On days when hematology is required 
for both safety and response 
assessments, samples should also be 
submitted to the central laboratory 
Blood chemistries 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter 
X 
X 
 
• Blood chemistry from serum or plasma 
should include assessment of: sodium, 
potassium, chloride, glucose, creatinine, 
total protein, albumin, total bilirubin, 
ALT and AST 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
• LDH, calcium, magnesium, phosphorus 
and uric acid are required at Screening 
and Day 1 of C1 to C6 
• Refer to Section 8.4.4.10 for hepatic 
safety monitoring 
• Screening results within 3 days of C1D1 
are acceptable as C1D1 results 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 21 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
• Direct (or indirect) bilirubin should be 
performed any time total bilirubin is 
abnormal 
Coagulation panel 
X 
As clinically indicated 
 
• aPTT and PT (or INR)  
Hepatitis B/C 
active disease 
status 
X 
 
 
 
 
 
 
 
• HBV and HCV testing to determine if 
patients have active infection 
• Refer to Section 5.2 for exclusions 
Serum or urine 
pregnancy test 
(WOCBP only) 
X 
X 
 
X 
C7D1 and 
Q12W 
thereafter  
 
 
 
• Perform within 24 hours of first dose of 
study treatment, and as indicated in 
table, or as required per local 
regulations and/or institutional 
guidelines  
• Refer to Section 10.2, Appendix 2 
Urinalysis 
X 
X 
As clinically indicated 
 
Dipstick analysis is acceptable and should 
include color, specific gravity, pH, 
glucose, bilirubin, occult blood, protein, 
leukocytes, and urobilinogen 
Documentation or sampling of the following are required during Screening, but results not required prior to enrollment 
β2 microglobulin 
X 
 
 
 
 
 
 
 
 
Serum 
immunoglobulins 
X 
 
 
 
 
 
 
IgG, IgA, IgM 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 22 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
Bone marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood 
assessment. Optional to confirm PD 
• 
 biopsy 
 required at 
Screening and for confirmation of CR  
CT or MRI 
X 
 
 
C4D1 
C7D1 and 
Q12W 
thereafter  
X 
 
X 
• Refer to Section 8.3 for details 
• CT scan with IV contrast agent is the 
preferred method of assessment with 
scans of neck, chest, abdomen, and 
pelvis. However, MRI is acceptable if 
CT scan with contrast agent is 
contraindicated 
• All response assessments should occur 
at Q12W intervals relative to C1D1 
regardless of any treatment delays or 
interruptions 
• At the EOT visit, a repeat CT/MRI does 
not need to be performed if done within 
the proceeding 2 weeks, or if PD was 
previously determined 
• A central radiology vendor will be used 
to collect and store images for IRC 
review 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 23 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
Pirtobrutinib 
administration 
 
X 
X 
X 
X 
X 
 
 
• 200 mg PO administered QD 
(continuous) 
• C1D1 should occur within 3 business 
days after randomization 
• Date of last dose and date of decision for 
end of treatment must be recorded in 
EDC 
Patient dosing 
diary 
 
X 
X 
X 
X 
X 
 
 
 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 24 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 6.5 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
 
• Collect SAEs from the time of ICF 
signing through 28 days after the last 
dose (NCI CTCAE v5.0) 
• Collect AEs from the time of dosing 
through SFU; AEs that occur prior to the 
first dose are considered medical history 
unless the AE develops or worsens due 
to study-related procedures 
• All SAEs occurring from the time ICF 
is signed through 28 days after the last 
dose must be reported to Clinical Safety 
within 24 hours of knowledge of the 
event. All SAEs that the Investigator 
considers related to study drug 
occurring after the 28-day follow-up 
period must be reported to the Sponsor 
• Second primary malignancy (SPM) 
events are to be reported and should 
continue to be reported for up to 5 years 
from the start of study treatment, 
regardless of seriousness or causal 
attribution to treatment (Section 8.5.8) 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 25 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 
2 years 
after last 
dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD  
Medical resources 
utilization 
 
X 
X 
X 
X 
X 
X 
 
Hospitalizations, emergency department 
visits, blood product transfusions, and 
hematopoietic growth factor use will be 
collected  
Patient reported 
outcomes 
 
X 
X 
X 
X 
X 
X 
 
Refer to Section 1.3.6 for details 
Survival status 
 
 
 
 
 
 
 
X 
 
• Survival information may be collected 
via telephone if no procedures are 
required; this information should be 
collected approximately Q12W after the 
SFU visit; refer to Section 6.7.5 
• Subsequent anticancer therapy 
information should be collected Q12W 
after the SFU visit for the first 2 years, 
and approximately Q24W thereafter 
until death or study completion 
 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 26 of 181 
1.3.2. 
Schedule of Assessments for Arm B: Idelalisib plus Rituximab 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
• The ICF must be signed before 
any protocol-specified 
procedures are performed; refer 
to Section 10.1.2 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
• All ongoing conditions and 
relevant past surgical and 
medical history should be 
collected; refer to Section 8.2 
• Malignancy history should be 
collected regarding disease 
under study, and any history of 
other malignancy 
• Prior therapy related to 
CLL/SLL would be collected as 
part of the medical history, 
including reason for prior 
covalent BTK discontinuation 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 27 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Documentation 
of diagnosis and 
relevant 
biomarkers 
X 
 
 
 
 
 
 
 
 
 
 
• Anonymized/redacted 
pathology report(s) confirming 
diagnosis of CLL required for 
eligibility 
• Reports regarding status of any 
known CLL relevant 
biomarkers should be provided 
if available (e.g., IGHV, TP53 
mutation, complex karyotype, 
del 11q, BTK mutation and 
PLCg2 mutation) 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter  
X 
X 
X 
• Complete PE includes height 
(only at Screening), weight, 
basic neurological examination 
and review of relevant 
symptoms at Screening; refer to 
Section 8.4.2 
• Symptom-directed PE should 
be limited to systems of 
primary relevance such as 
cardiovascular, respiratory, and 
those associated with tumor 
assessment (lymph nodes, liver, 
and spleen) and may be 
performed at other timepoints; 
include weight as clinically 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 28 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
indicated throughout the trial 
• Screening results obtained 
within 3 days of C1D1 are 
acceptable as C1D1 results  
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter  
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter  
X 
X 
 
• Includes systolic and diastolic 
blood pressure, heart rate, 
respiratory rate and body 
temperature  
Results of tests in the section below are required for eligibility determination and enrollment 
Deletion 17p 
evaluation 
X 
 
 
 
 
 
 
 
 
 
 
• Refer to Section 1.2.2 
• Results are required for 
stratification 
CMV 
X 
 
 
 
 
C4D1 
 
C7D1 and 
Q12W 
thereafter  
 
 
 
• CMV IgG, IgM and DNA PCR 
at Screening  
• CMV DNA PCR for 
monitoring (Section 8.4.4.5) 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
• Obtain ECGs at specified visit 
• Refer to Section 8.4.3 
• At Screening, single ECG 
should be collected 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 29 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Hematology 
X 
X 
X 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter  
X 
X 
X 
• Includes hemoglobin, 
hematocrit, RBC count, WBC 
count, platelet count, percent or 
absolute differential 
(neutrophils, lymphocytes, 
eosinophils, basophils, and 
monocytes) 
• Screening results obtained 
within 3 days of C1D1 are 
acceptable as C1D1 results 
• Repeat testing during Screening 
is permitted; refer to 
Section 5.5 
• On days when hematology is 
required for both safety and 
response assessments, samples 
should also be submitted to the 
central laboratory 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 30 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Blood 
chemistries 
X 
X 
X 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafter  
X 
X 
 
• Blood chemistry from serum or 
plasma should include 
assessment of: sodium, 
potassium, chloride, glucose, 
creatinine, total protein, 
albumin, total bilirubin, ALT, 
and AST 
• Repeat testing during Screening 
is permitted; refer to 
Section 5.5 
• LDH, calcium, magnesium, 
phosphorus and uric acid are 
required at Screening and Day 
1 of C1 to C6 
• Screening results within 3 days 
of C1D1 are acceptable as 
C1D1 results 
Coagulation 
panel 
X 
As clinically indicated 
 
aPTT and PT (or INR)  
Hepatitis B/C 
active disease 
status 
X 
 
 
 
 
 
 
 
 
 
 
• HBV and HCV testing to 
determine if patients have 
active infection 
• Refer to Section 5.2 for 
exclusions 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 31 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Serum or urine 
pregnancy test 
(WOCBP only) 
X 
X 
 
X 
 
X 
 
 C7D1 and 
Q12W 
thereafter  
 
 
 
• Perform within 24 hours of first 
dose of study treatment, and as 
indicated in table, or as 
required per local regulations 
and/or institutional guidelines 
• Refer to Section 10.2, 
Appendix 2 
Urinalysis 
X 
X 
As clinically indicated 
 
Dipstick analysis is acceptable 
and should include color, specific 
gravity, pH, glucose, bilirubin, 
occult blood, protein, leukocytes, 
and urobilinogen 
Documentation or sampling of the following are required during Screening, but results not required prior to enrollment 
β2 
microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum 
immunoglobulins 
X 
 
 
 
 
 
 
 
 
 
 
IgG, IgA, IgM 
Bone marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood assessment. Optional to 
confirm PD. 
• 
 biopsy 
 
required at Screening and for 
confirmation of CR  
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 32 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
CT or MRI 
X 
 
 
 
 
C4D1 
 
C7D1 and 
Q12W 
thereafter  
X 
 
X 
 
• Refer to Section 8.3 for details 
• CT scan with IV contrast agent 
is the preferred method of 
assessment with scans of neck, 
chest, abdomen, and pelvis. 
However, MRI is acceptable if 
CT scan with contrast agent is 
contraindicated 
• All response assessments 
should occur at Q12W intervals 
relative to C1D1 regardless of 
any treatment delays or 
interruptions 
• At the EOT visit, a repeat 
CT/MRI does not need to be 
performed if done within the 
proceeding 2 weeks, or if PD 
was previously determined  
• A central radiology vendor will 
be used to collect and store 
images for IRC review 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 33 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Idelalisib 
administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
• 150 mg PO administered BID 
(continuous)  
• C1D1 should occur within 
3 business days after 
randomization. 
• Date of last dose and date of 
decision for end of treatment 
must be recorded in EDC 
Rituximab 
administration 
 
375 
mg/m2 
500 mg/m2 Q2W for 4 infusions 
(C1D15, C2D1, C2D15, C3D1) and 
Q4W for 3 infusions (C4D1, C5D1, 
C6D1) 
 
 
 
 
 
• C1D1 should occur within 
3 business days after 
randomization. 
• Date of last dose and date of 
decision for end of treatment 
must be recorded in EDC 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 34 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Patient dosing 
diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 6.5 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
• Collect SAEs from the time of 
ICF signing through 28 days 
after the last dose (NCI CTCAE 
v5.0) 
• Collect AEs from the time of 
dosing through SFU; AEs that 
occur prior to the first dose are 
considered medical history 
unless the AE develops or 
worsens due to study-related 
procedures 
• All SAEs occurring from the 
time ICF is signed through 
28 days after the last dose must 
be reported to Clinical Safety 
within 24 hours of knowledge 
of the event. All SAEs that the 
Investigator considers related 
to study drug occurring after 
the 28-day follow-up period 
must be reported to the Sponsor 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 35 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
• Second primary malignancy 
(SPM) events are to be reported 
and should continue to be 
reported for up to 5 years from 
the start of study treatment, 
regardless of seriousness or 
causal attribution to treatment 
(Section 8.5.8) 
Medical 
resources 
utilization  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hospitalizations, emergency 
department visits, blood product 
transfusions, and hematopoietic 
growth factor use will be 
collected 
Patient-reported 
outcomes 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 1.3.6 for details 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 36 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit Window 
Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 
weeks) for up 
to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 
2 years for 
patients who 
discontinue 
prior to PD  
Survival status 
 
 
 
 
 
 
 
 
 
 
X  
• Survival information may be 
collected via telephone if no 
procedures are required; this 
information should be collected 
approximately Q12W after the 
SFU visit; refer to Section 6.7.5 
• Subsequent anticancer therapy 
information should be collected 
approximately Q12W after the 
SFU visit for the first 2 years 
and approximately Q24W 
thereafter until death or study 
completion 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 37 of 181 
1.3.3. 
Schedule of Assessments for Arm B: Bendamustine plus Rituximab  
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
Informed 
consent 
X 
 
 
 
 
 
 
 
The ICF must be signed before 
any protocol-specified procedures 
are performed. Refer to 
Section 10.1.2 
Medical history 
X 
 
 
 
 
 
 
 
• All ongoing conditions and 
relevant past surgical and 
medical history should be 
collected. Refer to Section 8.2 
• Malignancy history should be 
collected regarding disease 
under study and any history of 
other malignancy 
• Prior therapy related to 
CLL/SLL would be collected as 
part of the medical history, 
including reason for prior 
covalent BTK discontinuation 
Documentation 
of diagnosis and 
relevant 
biomarkers 
X 
 
 
 
 
 
 
 
• Anonymized/redacted 
pathology report(s) confirming 
diagnosis of CLL required for 
eligibility. 
• Reports regarding status of any 
known CLL relevant 
biomarkers should be provided 
if available (e.g., IGHV, TP53 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 38 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
mutation, complex karyotype, 
del 11q, BTK mutation and 
PLCg2 mutation) 
Physical 
examination 
X 
X 
 
X 
 
X 
X 
X 
• Complete PE includes height 
(only at Screening), weight, 
basic neurological examination, 
and review of relevant 
symptoms at Screening; refer to 
Section 8.4.2 
• Symptom-directed PE should 
be limited to systems of 
primary relevance such as 
cardiovascular, respiratory, and 
those associated with tumor 
assessment (lymph nodes, liver, 
and spleen) and may be 
performed at other timepoints; 
include weight as clinically 
indicated throughout the trial 
• Screening results obtained 
within 3 days of C1D1 are 
acceptable as C1D1 results  
ECOG PS 
X 
X 
 
X 
 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
• Includes systolic and diastolic 
blood pressure, heart rate, 
respiratory rate, and body 
temperature  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 39 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
Results of tests in the section below are required for eligibility determination and enrollment 
Deletion 17p 
evaluation 
X 
 
 
 
 
 
 
 
• Refer to Section 1.2.2 
• Results are required for 
stratification 
CMV 
X 
 
 
 
 
 
 
 
CMV IgG, IgM and DNA PCR at 
Screening only; Section 8.4.4.5 
12-lead ECG 
X 
 
 
 
 
 
 
 
• Obtain ECGs at specified visit 
• Refer to Section 8.4.3 
• At Screening, single ECG 
should be collected 
Hematology 
X 
X 
 
X 
 
X 
X 
X 
• Includes hemoglobin, 
hematocrit, RBC count, WBC 
count, platelet count, percent or 
absolute differential 
(neutrophils, lymphocytes, 
eosinophils, basophils, and 
monocytes).  
• Screening results obtained 
within 3 days of C1D1 are 
acceptable as C1D1 results 
• Repeat testing during Screening 
is permitted; refer to 
Section 5.5 
• On days when hematology is 
required for both safety and 
response assessments, samples 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 40 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
should also be submitted to the 
central laboratory 
Blood 
chemistries 
 
X 
X 
 
X 
 
X 
X 
 
• Blood chemistry from serum or 
plasma should include 
assessment of: sodium, 
potassium, chloride, glucose, 
creatinine, total protein, 
albumin, total bilirubin, ALT, 
and AST 
• Repeat testing during Screening 
is permitted; refer to 
Section 5.5 
• LDH, calcium, magnesium, 
phosphorus and uric acid are 
required at Screening and 
Day 1 of C1 to C6 
• Screening results within 3 days 
of C1D1 are acceptable as 
C1D1 results 
Coagulation 
panel 
X 
As clinically indicated 
aPTT and PT (or INR) 
Hepatitis B/C 
active disease 
status 
X 
 
 
 
 
 
 
 
• HBV and HCV testing to 
determine if patients have 
active infection 
• Refer to Section 5.2 for 
exclusions 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 41 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
Serum or urine 
pregnancy test 
(WOCBP only) 
X 
X 
 
X 
 
X 
 
 
• Perform within 24 hours of first 
dose of study treatment, and as 
indicated in table, or as required 
per local regulations and/or 
institutional guidelines 
• Refer to Section 10.2, 
Appendix 2 
Urinalysis 
X 
X 
As clinically indicated 
Dipstick analysis is acceptable 
and should include color, specific 
gravity, pH, glucose, bilirubin, 
occult blood, protein, leukocytes, 
and urobilinogen 
Documentation or sampling of the following are required during Screening, but results not required prior to enrollment 
β2 
microglobulin 
X 
 
 
 
 
 
 
 
 
Serum 
immunoglobulins 
X 
 
 
 
 
 
 
 
IgG, IgA, IgM 
Bone marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood assessment 
(required) and to confirm PD (optional) 
• 
 biopsy 
 
required at Screening and for 
confirmation of CR  
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 42 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
CT or MRI 
X 
 
 
C4D1 
 
X 
 
X  
• Refer to Section 8.3 for details 
• CT scan with IV contrast agent 
is the preferred method of 
assessment with scans of neck, 
chest, abdomen, and pelvis. 
However, MRI is acceptable if 
CT scan with contrast agent is 
contraindicated. 
• All response assessments 
should occur at Q12W intervals 
relative to C1D1 regardless of 
any treatment delays or 
interruptions 
• At the EOT visit, a repeat 
CT/MRI does not need to be 
performed if done within the 
proceeding 2 weeks, or if PD 
was previously determined 
• A central radiology vendor will 
be used to collect and store 
images for IRC review 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 43 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
Bendamustine 
administration - 
IV 
 
70 mg/m2 
70 mg/m2 
70 mg/m2 
70 mg/m2 
 
 
 
• C1D1 should occur within 
3 business days after 
randomization 
•  Date of last dose and date of 
decision for end of treatment 
must be recorded in EDC 
Rituximab 
administration - 
IV 
 
375 
mg/m2 
 
500 mg/m2 
Day 1 of 
Cycles 2-6 
 
 
 
 
• C1D1 should occur within 
3 business days after 
randomization 
•  Date of last dose and date of 
decision for end of treatment 
must be recorded in EDC 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 6.5 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
 
• Collect SAEs from the time of 
ICF signing through 28 days 
after the last dose (NCI CTCAE 
v5.0) 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 44 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
• Collect AEs from the time of 
dosing through SFU; AEs that 
occur prior to the first dose are 
considered medical history 
unless the AE develops or 
worsens due to study-related 
procedures 
• All SAEs occurring from the 
time ICF is signed through 
28 days after the last dose must 
be reported to Clinical Safety 
within 24 hours of knowledge 
of the event. All SAEs that the 
Investigator considers related to 
study drug occurring after the 
28-day follow-up period must 
be reported to the Sponsor 
• Second primary malignancy 
(SPM) events are to be reported 
and should continue to be 
reported for up to 5 years from 
the start of study treatment, 
regardless of seriousness or 
causal attribution to treatment 
(Section 8.5.8) 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 45 of 181 
Arm B: Bendamustine plus Rituximab (BR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1  
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
Medical 
resources 
utilization 
 
X 
X 
X 
X 
X 
X 
 
Hospitalizations, emergency 
department visits, blood product 
transfusions, and hematopoietic 
growth factor use will be 
collected 
Patient-reported 
outcomes 
 
X 
X 
X 
X 
X 
X 
 
Refer to Section 1.3.6 for details 
Survival 
 
 
 
 
 
 
 
X 
• Survival information may be 
collected via telephone if no 
procedures are required; this 
information should be collected 
approximately Q12W after the 
SFU visit; refer to Section 6.7.5 
• Subsequent anticancer therapy 
information should be collected 
approximately Q12W after the 
SFU visit for the first 2 years 
and approximately Q24W 
thereafter until death or study 
completion 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 46 of 181 
1.3.4. 
Schedule of Assessments for Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
NOTES: 
This SoA is applicable only for patients who were initially randomly assigned to Arm B (Investigator’s choice), who have PD that is 
confirmed by the IRC, who are eligible for crossover (CO) treatment (refer to Section 5.3 Eligibility Criteria for Crossover 
Treatment), and have elected for optional crossover. 
Patients who cross over will complete the Arm B End of Treatment (EOT) before crossing over to Arm A. Testing and assessments 
that are performed as part of Arm B, and that are within the Screening window of up to 42 days, do not need to be repeated as a part of 
the Screening evaluation for crossover. 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-
Cycle 1 
CO-
Cycle 4 
and 
higher 
CO-EOT 
CO-SFU 
CO-
LTFU 
Visit Window 
Up to 42 
days 
Day 1 
± 14 Days 
+14 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q24W 
(± 4 weeks)  
Informed 
consent 
X 
 
 
 
 
 
• The ICF for crossover must be signed before any protocol-
specified procedures are performed. Refer to Section 10.1.2 
• Crossover screening procedures must be completed within 
42 days of IRC-confirmed PD  
Physical 
examination 
X 
X 
CO-C7D1 
and Q24W 
thereafter 
X 
X 
X 
• Complete PE includes height (only at Screening), weight, basic 
neurological examination and review of relevant symptoms at 
Screening (refer to Section 8.4.2) 
• Symptom-directed PE should be limited to systems of primary 
relevance such as cardiovascular, respiratory, and those 
associated with tumor assessment (lymph nodes, liver, and 
spleen) and may be performed at other timepoints; include 
weight as clinically indicated throughout the trial 
• Screening results obtained within 3 days of CO-C1D1 are 
acceptable as CO-C1D1 results 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 47 of 181 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-
Cycle 1 
CO-
Cycle 4 
and 
higher 
CO-EOT 
CO-SFU 
CO-
LTFU 
Visit Window 
Up to 42 
days 
Day 1 
± 14 Days 
+14 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q24W 
(± 4 weeks)  
ECOG PS 
X 
X 
CO-C7D1 
and Q24W 
thereafter 
X 
X 
 
 
Vital signs 
X 
X 
CO-C7D1 
and Q24W 
thereafter 
X 
X 
 
• Includes systolic and diastolic blood pressure, heart rate, 
respiratory rate and body temperature 
Results of tests in the section below are required for crossover eligibility determination 
12-lead ECG 
X 
  
 
 
 
 
• Obtain ECGs at specified visits and when patients are 
symptomatic. Refer to Section 8.4.3 
• ECGs should be collected: 
− At Screening, single ECG  
− If an unscheduled ECG is done at any time, an electrolyte 
panel (i.e., calcium, magnesium, and potassium) must be done 
to coincide with the ECG 
− If a clinically significant arrhythmia is detected, details must 
be in EDC 
Hematology 
X 
X 
CO-C7D1 
and Q24W 
thereafter 
X 
X 
X 
• Includes hemoglobin, hematocrit, RBC count, WBC count, 
platelet count, percent or absolute differential (neutrophils, 
lymphocytes, eosinophils, basophils, and monocytes) 
• Screening results obtained within 3 days of C1D1 are acceptable 
as C1D1 results 
• Repeat testing during Screening is permitted; refer to Section 5.5 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 48 of 181 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-
Cycle 1 
CO-
Cycle 4 
and 
higher 
CO-EOT 
CO-SFU 
CO-
LTFU 
Visit Window 
Up to 42 
days 
Day 1 
± 14 Days 
+14 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q24W 
(± 4 weeks)  
Blood 
chemistries 
X 
X 
CO-C7D1 
and Q24W 
thereafter 
X 
X 
 
• Blood chemistry from serum or plasma should include 
assessment of: Sodium, potassium, chloride, glucose, creatinine, 
total protein, albumin, total bilirubin, ALT, and AST 
• Repeat testing during Screening is permitted; refer to Section 5.5 
• Tests for LDH, calcium, magnesium, phosphorus and uric acid 
are only required on Day 1 of CO-C1  
• Screening results within 3 days of CO-C1D1 are acceptable as 
CO-C1D1 results 
• Direct (or indirect) bilirubin should be performed any time total 
bilirubin is abnormal 
Coagulation 
panel 
X 
As clinically indicted 
 
aPTT and PT (or INR) 
Serum or urine 
pregnancy test 
(WOCBP only) 
X 
X 
 CO-C7D1 
and Q24W 
thereafter 
 
 
 
Perform within 24 hours of first dose of study treatment, and as 
indicated in table, or as required per local regulations and/or 
institutional guidelines. Refer to Section 10.2  
Urinalysis 
X 
As clinically indicated 
 
 
 
Dipstick analysis is acceptable and should include color, specific 
gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, 
and urobilinogen 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 49 of 181 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-
Cycle 1 
CO-
Cycle 4 
and 
higher 
CO-EOT 
CO-SFU 
CO-
LTFU 
Visit Window 
Up to 42 
days 
Day 1 
± 14 Days 
+14 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q24W 
(± 4 weeks)  
Documentation or sampling of the following are required during Screening, but results not required prior to initiation of Pirtobrutinib 
CT or MRI 
X 
 
CO-C7D1 
and Q24W 
thereafter 
X 
 
X 
• Refer to Section 8.1 for details. 
• If baseline CT or MRI assessment documenting PD by IRC was 
performed within 42 days of planned C1D1, a new scan does not 
need to be obtained 
• All response assessments should occur at Q24W intervals 
relative to CO-C1D1, regardless of any treatment delays or 
interruptions 
• At the EOT visit, a repeat CT/MRI does not need to be 
performed if done within the proceeding 2 weeks or if PD was 
previously determined 
• Investigator assessment of CT or MRI will be done locally at 
frequency of at least Q24W frequency or based on standard of 
care 
Pirtobrutinib 
administration  
 
X 
X 
X 
 
 
• 200 mg PO administered QD (continuous) 
• Crossover treatment should be initiated within a window of 
42 days after the IRC-confirmed PD 
• Patient to visit study site Q12W from CO-C4D1 for dispensation 
of pirtobrutinib 
• Date of last dose and date of decision to end treatment must be 
recorded in EDC prior to patient receiving first dose of treatment 
in crossover 
Patient dosing 
diary 
 
X 
X 
 
 
 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 50 of 181 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-
Cycle 1 
CO-
Cycle 4 
and 
higher 
CO-EOT 
CO-SFU 
CO-
LTFU 
Visit Window 
Up to 42 
days 
Day 1 
± 14 Days 
+14 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q24W 
(± 4 weeks)  
Adverse events 
X 
X 
X 
X 
X 
 
• Collect SAEs from the time of ICF signing through 28 days after 
the last dose (NCI CTCAE v5.0) 
• Collect AEs from the time of dosing through SFU; AEs that 
occur prior to the first dose are considered medical history 
unless the AE develops or worsens due to study-related 
procedures 
• All SAEs occurring from the time ICF is signed through 28 days 
after the last dose must be reported to Clinical Safety within 
24 hours of knowledge of the event. All SAEs that the 
Investigator considers related to study drug occurring after the 
28-day follow-up period must be reported to the Sponsor 
• Second primary malignancy (SPM) events are to be reported and 
should continue to be reported for up to 5 years from the start of 
pirtobrutinib treatment, regardless of seriousness or causal 
attribution to pirtobrutinib treatment 
Survival status 
 
X 
X 
X 
X 
X 
• Survival information may be collected via telephone if no 
procedures are required; survival information should be 
collected approximately Q24W after the SFU visit; refer to 
Section 6.7.5 
• Subsequent anticancer therapy information should be collected 
Q24W after the SFU visit until death or study completion 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 51 of 181 
1.3.5. 
Schedule of Assessments for Response Assessments, Arms A and B (Does not Apply for Crossover)  
NOTE: This section is a guide to specify elements required for response assessment without duplicating activities in the SoAs above. 
Assessments should include disease and symptom-focused physical examination, imaging, and hematology results and bone marrow 
examinations as described in iwCLL 2018.  
Response Assessments, Arms A and B (does not apply for crossover) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 +  
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 28 
days 
Day 1  
(± 7 Days) 
+ 7 days of last 
dose or decision 
to terminate 
treatment 
28 days 
 (+ 7 days) after last 
dose or decision to 
terminate treatment 
Q12W (± 4 weeks) for up 
to 2 years after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who discontinue 
prior to PD 
Bone marrow 
 
biopsy 
X 
Within 4-8 weeks of confirmed CR 
by scan and peripheral blood 
assessment. Optional to confirm PD 
 
 
• 
 biopsy 
 required at Screening and 
for confirmation of CR  
CT or MRI 
X 
C4D1 and Q12W 
thereafter 
X 
 
X 
 
• Refer to Section 8.3.1 for details 
• CT scan with IV contrast agent is the preferred 
method of assessment with scans of neck, chest, 
abdomen, and pelvis. However, MRI is acceptable 
if CT scan with contrast agent is contraindicated 
• All response assessments should occur at Q12W 
intervals relative to C1D1 regardless of any 
treatment delays or interruptions 
• At the EOT visit, a repeat CT/MRI does not need 
to be performed if done within the proceeding 
2 weeks or if PD was previously determined 
• A central radiology vendor will be used to collect 
and store images for IRC review 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 52 of 181 
Response Assessments, Arms A and B (does not apply for crossover) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 +  
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 28 
days 
Day 1  
(± 7 Days) 
+ 7 days of last 
dose or decision 
to terminate 
treatment 
28 days 
 (+ 7 days) after last 
dose or decision to 
terminate treatment 
Q12W (± 4 weeks) for up 
to 2 years after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who discontinue 
prior to PD 
Physical 
Examination 
X 
C4D1 and Q12W 
thereafter 
X 
 
X 
• Complete PE includes height (only at Screening), 
weight, basic neurological examination, and 
review of relevant symptoms at Screening; refer 
to Section 8.4.2 
• Symptom-directed PE should be limited to 
systems of primary relevance such as 
cardiovascular, respiratory, those associated with 
symptoms, and those associated with tumor 
assessment (lymph nodes, liver, and spleen) and 
may be performed at other timepoints; include 
weight as clinically indicated throughout the trial 
Hematology 
X 
C4D1 and Q12W 
thereafter 
X 
 
X 
• Includes hemoglobin, hematocrit, RBC count, 
WBC count, platelet count, percent or absolute 
differential (neutrophils, lymphocytes, 
eosinophils, basophils, and monocytes) 
• Screening results obtained within 3 days of C1D1 
are acceptable as C1D1 results 
• Repeat testing during Screening is permitted; 
refer to Section 5.5 
• On days when hematology is required for both 
safety and response assessments, samples should 
also be submitted to the central laboratory 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 53 of 181 
1.3.6. 
Schedule of Assessments for Patient-Reported Outcomes, Arms A and B 
Instrument 
 
Cycle 1 
Complete until EOT 
EOT 
SFU 
Instructions 
Visit Window 
Day 1 
(Completed in 
clinic prior to 
first dose of 
study drug) 
Every 4 Weeks 
± 7 days 
Every 12 Weeks 
± 7 days 
+ 7 days of last 
dose or 
decision to 
terminate 
treatment 
 28 days 
(+7 days) after 
last dose or 
decision to 
terminate 
treatment 
EORTC QLQ-C30  
X 
 
X 
X 
X 
• All PRO assessments 
must be completed 
electronically. 
• Refer to Section 8.12.1 
for more details. 
EORTC IL19 
(Physical Function) 
 
Xa 
 
 
 
EQ-5D-5L  
X 
 
X 
X 
X 
a This instrument will not be administered on weeks where the EORTC QLQ-C30 and EORTC 
 are administered due to overlapping items.  
  
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 54 of 181 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
Pirtobrutinib is an orally available, highly selective, ATP-competitive inhibitor of BTK distinct 
from the approved BTK inhibitors (ibrutinib approved globally for CLL/SLL and MCL; 
acalabrutinib approved in select countries for CLL/SLL and MCL; zanubrutinib approved in the 
US for CLL and MCL) on the basis of its selectivity, favorable pharmacologic and PK 
properties, and non-covalent binding mode (Brandhuber et al. 2018). In a Phase 1/2 study 
(LOXO-BTK-18001, NCT03740529), pirtobrutinib has demonstrated robust and durable 
antitumor activity against a variety of B-cell malignancies including CLL/SLL, regardless 
of prior treatment and including in patients previously treated with covalent BTK inhibitors.  
The proposed Phase 3 study is a global, randomized, open-label study in patients with previously 
treated CLL/SLL who have received a prior covalent BTK inhibitor to assess the superiority of 
pirtobrutinib to Investigator’s choice of either idelalisib with rituximab (IdelaR) or bendamustine 
with rituximab (BR). The proposed study will uniquely evaluate the role of non-covalent BTK 
inhibitor therapy in a prospectively identified CLL/SLL patient population pretreated with prior 
covalent BTK inhibitors.  
2.2. 
Background 
BTK is a member of the TEC family of non-receptor tyrosine kinases (which includes BTK, 
ITK, TEC, TXK, and BMX) and a key component of the B-cell receptor (BCR) signaling 
complex. BTK also plays a critical role in the proliferation and survival of diverse B-cell 
malignancies.  
BTK inactivating mutations were originally identified as the cause of X-linked 
immunodeficiency (Xid) in mice (Rawlings et al. 1993; Thomas et al. 1993) and X-linked 
agammaglobulinemia (XLA) in humans (Vetrie et al. 1993). XLA is a rare, X-linked recessive 
disorder that causes severe bacterial infections in affected boys due to a complete absence of 
functional B lymphocytes and antibodies (Hendriks et al. 2011). Lifelong treatment with 
antibiotic prophylaxis and IV and/or subcutaneous (SC) immunoglobulins can prevent infection 
and lead to normal life expectancy. 
In normal B-cells, antigen binding to the BCR leads to activation of the upstream kinases LYN 
and SYK, recruitment of phosphoinositide 3-kinase (PI3K), generation of the second messenger 
phosphatidylinositol 3-phosphate (PIP3) and PIP3-dependent recruitment of BTK to the plasma 
membrane. LYN and SYK-mediated phosphorylation of BTK on tyrosine residue 551 (Y551) 
stimulates the kinase activity of BTK, leading to autophosphorylation on Y223 and 
phosphorylation-dependent activation of the critical downstream signaling effector 
phospholipase C gamma 2 (PLCg2). PLCg2-mediated generation of second messengers inositol 
3-phosphate (IP3) and diacyl glycerol (DAG) induces the activation of several critical signaling 
effectors (nuclear factor of activated T-cells [NFAT], mitogen-activated protein kinase 
[MAPK]/extracellular signal-regulated kinase [ERK], protein kinase C [PKC], nuclear factor 
kappa-light-chain-enhancer of activated B-cells [NF-kB]) which results in increased proliferation 
and survival.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 55 of 181 
BTK expression is restricted to a subset of B-cells and myeloid cells, and in malignancies 
thought to derive from them, including CLL, related to naïve B-cells, MCL, marginal zone 
lymphoma (MZL, each related to germinal center B-cells), and Waldenström’s 
macroglobulinemia (WM, plasma cells). Consistent with a critical survival role for BTK in these 
malignancies, BTK deficiency abrogates tumor formation in CLL mouse models 
(Kil et al. 2013), and treatment of primary, patient-derived CLL, MCL and WM cells with the 
irreversible BTK inhibitor ibrutinib reduces their viability, adhesion and migration 
(Herman et al. 2011; Chang et al. 2013; Yang et al. 2013). 
Three BTK inhibitors are now approved for the treatment of patients with B-cell malignancies. 
These agents have altered the treatment paradigms for many B-cell malignancies, including 
CLL/SLL (ibrutinib, acalabrutinib, and zanubrutinib), relapsed/refractory (r/r) MCL (ibrutinib, 
acalabrutinib, and zanubrutinib), WM (ibrutinib, zanubrutinib), and MZL (ibrutinib, 
zanubrutinib). These agents potently inhibit BTK by binding to the ATP pocket of the enzyme 
and forming an irreversible, covalent bond with the C481 in the BTK enzyme. Covalent ligation 
of BTK inhibits its kinase activity, induces BTK degradation and causes potent and prolonged 
BTK target engagement and inhibition in patients (Byrd et al. 2013; Byrd et al. 2016). Treatment 
with other, investigational irreversible BTK inhibitors has produced near total BTK suppression 
in circulating leukemia cells and lymphoma/leukemia lymph node reservoirs and has induced 
significant tumor responses (Tam et al. 2015). However, ibrutinib, acalabrutinib, and 
zanubrutinib are covalent inhibitors with limited oral bioavailability, high protein binding, and 
half-lives that are significantly shorter than their dosing intervals. The clinical efficacy of these 
agents is therefore attributed to their irreversible binding mode at the C481. Once bound to BTK, 
these agents require protein turnover to “undo” their pharmacodynamic effects of inhibition. 
Reliance on covalent binding may lead to diminished target coverage towards the end of the 
dosing interval (i.e., low trough coverage) and in rapidly proliferating tumors with higher BTK 
protein turnover with subsequent loss of clinical activity.  
Although irreversible BTK inhibitors have transformed the treatment of several B-cell 
malignancies, their long-term efficacy is ultimately limited by toxicity and acquired resistance. 
In r/r CLL, although initial response rates to ibrutinib are high, rates of treatment discontinuation 
are also high (approximately 40%) with extended follow-up (Woyach et al. 2017; 
Mato et al. 2018). The most common reasons for treatment discontinuation are AEs in 
approximately 50 to 60%, CLL progression in approximately 20 to 30%, and Richter’s 
Transformation in approximately 5 to 15% of patients. Toxicities of ibrutinib that lead to dose 
interruptions and treatment discontinuation include arthralgia, atrial fibrillation, rash, cytopenias, 
infection, pneumonitis, bleeding and diarrhea (Mato et al. 2018). These toxicities have been 
attributed to both on-target BTK inhibition and off-target inhibition of other kinases such as TEC 
(McMullen et al. 2014; Kamel et al. 2015). Acalabrutinib, which is more selective than ibrutinib 
against non-BTK kinase off-targets in preclinical studies, has been associated with a lower 
overall frequency of some (e.g., atrial fibrillation, major bleeding), but not other (e.g., 
cytopenias, upper respiratory infection, diarrhea) toxicities in clinical trials (Byrd et al. 2013; 
Byrd et al. 2016). A retrospective analysis of the RESONATE study indicated worse PFS in 
patients with r/r CLL with lower ibrutinib dose intensity and dose interruptions lasting for longer 
than 7 days, suggesting that treatment interruptions for toxicity can adversely impact long-term 
outcomes (Barr et al. 2017).  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 56 of 181 
Recent analysis of primary CLL samples from patients with relapsed CLL who responded to, but 
then ultimately progressed on ibrutinib, has uncovered 2 primary mechanisms of acquired 
resistance, and one less common: substitution at C481, primarily with a serine residue 
(i.e., C481S) in the majority (67%) of patients, which prevent irreversible binding of ibrutinib 
(and acalabrutinib) to BTK; activating mutations in PLCg2, a critical signaling effector 
downstream of BTK in 13%; and less commonly, both mutations occurring in the same patient 
(7%) (Woyach et al. 2017). These frequencies have been validated in more recent studies 
(Bonfiglio et al. 2018). Other studies have uncovered C481 substitution mutations in WM and 
MCL, indicating that C481 substitutions represent a common mechanism of “on target” 
resistance to irreversible BTK inhibitors in patients (Chiron et al. 2014; Xu et al. 2017). 
C481 substitutions prevent irreversible ligation of ibrutinib (and other irreversible BTK 
inhibitors) to BTK. These mutations lead to insufficient BTK target coverage in patients 
and treatment failure as a result (Byrd et al. 2013; Woyach et al. 2017). 
2.2.1. 
Current Approaches to Treatment of CLL/SLL 
CLL/SLL is the most common form of adult leukemias in the Western world and accounts for 
approximately 30-40% of all leukemias (Wierda et al. 2020; Eichhorst et al. 2015). SLL defines 
the same disease manifesting predominantly in lymph nodes instead of as leukemia. The median 
age at diagnosis has variously been reported as between 67 and 72 years of age with male 
predominance (Watson et al. 2008; 2014 Review of Cancer Medicines [WHO]). CLL/SLL 
occurs in approximately 3.8-4.2 in 100,000 people in Europe (Sant et al. 2010; 
Eichhorst et al. 2015) and 4.5 in 100,000 people per year in the United States (US) 
(Howlader et al. 2020). Allogeneic stem cell transplantation (SCT) is the only known curative 
therapy, but with limited applicability to the typical patient diagnosed with CLL/SLL who 
generally is older with co-morbidities. Thus, treatment is not given with intent to cure and while 
many patients do not need treatment at diagnosis, once initiated, sequential treatments are the 
standard to extend survival. Ongoing efforts to identify therapies which can contribute to the 
meaningful improvement of patient outcomes are needed. 
For newly diagnosed CLL/SLL, BTK inhibition (with zanubrutinib, ibrutinib, or acalabrutinib), 
chemo-immunotherapy, or BCL2 inhibition (with venetoclax) are approved standard treatments 
in select countries. The selection of one strategy over another is highly influenced by patient age, 
comorbid illness, prognostic markers, patient preference, and treatment setting. BTK inhibitors 
are becoming the preferred first-line therapy and have meaningfully impacted PFS and OS 
compared to chemoimmunotherapy (Shanafelt et al. 2019). Importantly, however, frontline BTK 
inhibitor-based therapies are not curative, and patients eventually relapse. Following progression 
on BTK inhibitors, median OS in one recent study was only 22.7 months, demonstrating an 
ongoing unmet need for this population (Woyach et al. 2017). 
Prospective data evaluating treatment for relapsed CLL after BTK inhibitor is scarce and the data 
used to support the global marketing authorisations for treatments in the relapsed CLL setting 
were conducted in patients who were almost exclusively BTK inhibitor naïve. In a recent interim 
analysis of an ongoing Phase 1 study, treatment of CLL patients who had failed prior ibrutinib 
treatment with the targeted BCL2 inhibitor venetoclax achieved an ORR of 65% (9% CR) 
(Mato et al. 2018). Recent data of venetoclax with rituximab therapy in the relapsed setting has 
introduced the concept of treatment given for a defined fixed-duration, in contrast to the 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 57 of 181 
continuous daily administration required for BTK inhibitor monotherapy given for the same 
indication. These data show the promise of this approach by inducing deep responses as 
evidenced by the high percentage of patients with high clearance rate of minimal residual disease 
which correlates with improved PFS (Seymour et al. 2018; Kater et al. 2018). However, despite 
this encouraging activity, venetoclax with rituximab does not yet define a cure with extended 
follow-up. Of importance, only 8 of 389 total enrolled patients had received a prior BCR 
inhibitor with even fewer receiving prior BTK inhibitors.  
Thus, few effective salvage therapy options currently available have been evaluated specifically 
for patients who have progressed on irreversible BTK inhibitors. The ORR of treatments for this 
population are garnered from varied retrospective reports ranges from 28% to 70% and identify 
an ongoing need for new therapies (Mato et al. 2017; Mato et al. 2016; Jain et al. 2015). 
Therefore, while some post-marketing data in BTK inhibitor-treated patients have been 
collected, the data from such analyses are not incorporated into existing prescribing information 
and for this reason, the true efficacy of options for pretreated CLL after a BTK inhibitor remains 
investigational. Although durable remissions with CD19-specific chimeric antigen receptor-
modified T-cells (CAR-T) after ibrutinib failure have been observed, CAR-T therapy as a whole 
appears less efficacious in CLL than in aggressive B-cell malignancies (e.g., acute leukemias and 
aggressive non-Hodgkin lymphomas [NHL]) and is associated with significant toxicities 
(Turtle et al. 2017). 
Chemotherapy has been a mainstay of treatment for CLL therapy prior to the introduction 
of inhibitors of the B-cell receptor and remains a treatment option. Chlorambucil was the 
primary chemotherapy for treatment of CLL until the superiority of bendamustine monotherapy 
was demonstrated in the relapsed settings on the basis of multicenter, international study 
(Bergmann et al. 2005). The combination of bendamustine with rituximab (BR) for a treatment 
duration of only 6 cycles was established as a treatment option for relapsed CLL in 2011 
(Fischer et al. 2011). Data from an observational study on the efficacy of BR as first salvage 
therapy in CLL identified a median PFS of 25 months, but the presence of del 17p, unmutated 
immunoglobulin heavy chain variable region gene (IGHV), and advanced disease stage were 
associated with shorter PFS (Cuneo et al, 2018). The same analysis evaluated outcomes in a 
matched indirect comparison of second line BR against ibrutinib in patients treated with frontline 
chemoimmunotherapy and restricted to those with intact 17p, and no OS difference was 
identified. When given in later lines of treatment, response to BR declines, but complete 
remissions can still be attained (Pound et al. 2011) Thus, BR is an effective time-limited salvage 
therapy for relapsed CLL, particularly for patients without del 17p.  
Idelalisib is a selective inhibitor of PI3K-δ approved in the US and Europe in 2014 in 
combination with rituximab for relapsed CLL and in 1L for the high risk del 17p/TP53 mutated 
group, but only if patients are not eligible for other frontline therapies as the toxicity profile of 
idelalisib can be restrictive and include pneumonitis, colitis, Grade 3 or higher rash, and elevated 
transaminases. These toxicities appear to be immune-mediated and reflect suppression of T-cell 
mediated self-tolerance by inhibition of PI3K-δ (Patton et al. 2006). These toxicities are 
heightened with idelalisib given in the frontline setting while idelalisib with rituximab appears to 
harbor a more acceptable safety profile in the relapsed treatment setting for CLL due to lower 
T-cell counts. Although data leading to the approval of idelalisib with rituximab in relapsed CLL 
did not include patients previously treated with BTK inhibitors, the common usage of IdelaR has 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 58 of 181 
been limited by the toxicity profile and typically follows ibrutinib and venetoclax, particularly 
for patients harboring del 17p (Schenkel et al. 2017; Mato et al. 2019).  
For the proposed Phase 3 study the comparator arm will be Investigator’s choice of either 
idelalisib in combination with rituximab or bendamustine in combination with rituximab. Both 
comparators are recognized by European Society for Medical Oncology (ESMO) and National 
Comprehensive Cancer Network (NCCN) as treatment options for patients with relapsed or 
refractory CLL, and both regimens are globally acceptable standard therapies with wide 
availability. Data on the selected comparators of idelalisib plus rituximab and bendamustine plus 
rituximab treatments suggest similar efficacy data to allow either option to be offered as a 
control arm for this Phase 3 study. For bendamustine plus rituximab, ORR is reported as 66 to 
68% with median PFS 14 to 17 months (Seymour et al. 2018; Fraser et al. 2019) and for 
idelalisib with rituximab, ORR is 84% with median PFS of 19 months (Sharman et al. 2019). As 
the comparator arm does not include BCL2 inhibitor-based therapy as an option, the Sponsor 
anticipates that a substantial number of patients will have already received prior venetoclax prior 
to enrolling to this clinical trial. Thus, the expectation is that this study will enroll not only 
patients who have received a prior covalent BTK inhibitor, but also a substantial number of 
patients who have also received a BCL2 inhibitor. This study will therefore help establish the 
risk/benefit profile of pirtobrutinib, as well as the control arm, in this patient population where, 
to the Sponsor’s knowledge, no prospective efficacy data currently exist. Based on current 
available therapies, current practice, and regulatory approvals, both chemoimmunotherapy 
(with BR) or PI3K-based therapy (with IdelaR) are therefore deemed appropriate treatment 
regimen in this population, and hence are included in the control arm providing the patients and 
treating physician optionality to choose the most appropriate agent class for each patient based 
individualized risk/benefit assessment (Fischer et al. 2019; Hillmen et al. 2019; 
Seymour et al. 2018).  
2.3. 
Benefit/Risk Assessment 
Pirtobrutinib has demonstrated clinical activity in the patient population specified for this study. 
The LOXO-BTK-18001 (NCT03740529) is a first-in-human global Phase 1/2 study evaluating 
the safety and efficacy of pirtobrutinib in patients with CLL/SLL and B-cell NHL who have 
failed or are intolerant to standard-of-care therapy. The study commenced enrollment in 
March 2019 to establish the safety of pirtobrutinib, assess PK, and identify a recommended 
Phase 2 dose (RP2D) and a maximal tolerated dose (MTD). During Phase 1 dose escalation, 
pirtobrutinib was well tolerated at dose levels of 
 to 300 mg QD with no dose-limiting 
toxicities (DLTs). Given the totality of efficacy, clinical PK, and safety data, the Sponsor and 
Safety Review Committee decided that ongoing dose escalation was not medically justified and 
therefore, no MTD was established. An RP2D was identified as 200 mg QD. 
PK data show that pirtobrutinib is absorbed after oral administration with a median time to 
maximum plasma concentration (Tmax) of approximately 2 hours and low clearance. Plasma 
halflife appears to be approximately 20 hours. Steady-state AUC0-24 increase in approximate 
proportion with daily dose. 
 
 
 
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 59 of 181 
Study results from a 
 study 
 evaluating the 
 
 of pirtobrutinib showed that 
 
 
 
Efficacy data from the LOXO-BTK-18001 study show robust and durable antitumor activity 
against a variety of B-cell malignancies, including pretreated CLL/SLL. Enrolled patients have 
varied prior therapies, including diverse combinations of chemotherapy, anti-CD20 antibodies, 
BCL2 inhibitors, PI3K inhibitors, and BTK inhibitors. The vast majority of CLL/SLL patients 
treated on the LOXO-BTK-18001 study received a prior BTK inhibitor. Antitumor activity has 
been seen in the majority of patients, regardless of prior treatment, including in patients treated 
with covalent BTK inhibitors. Of note, durable objective responses have been seen in patients 
with acquired resistance to prior BTK therapy, regardless of BTK C481 mutational status. 
As of 27 September 2021, clinical safety data are available from a total of 679 patients treated 
with pirtobrutinib in Phase 1/2 Study LOXO-BTK-18001. This includes 654 patients treated at 
doses ranging from 
 QD to 300 mg QD in Phase 1/2 Monotherapy cohorts and 25 patients 
in the Phase 1b Combination Therapy arms (including 15 patients in Arm A [pirtobrutinib plus 
venetoclax] and 10 patients in Arm B [pirtobrutinib plus rituximab and venetoclax]). Nearly half 
of treated patients were patients with CLL/SLL (326 patients, 48.0%). Treatment-emergent 
adverse events (TEAEs) were reported in 617 of the 679 treated patients (90.9%) in the study.  
In the 654 patients in the Phase 1/2 Monotherapy cohorts in Study LOXO-BTK-18001, the most 
frequently reported TEAEs were fatigue (24.2% total, 9.6% related), diarrhea (19.1% total, 8.3% 
related), and contusion (17.1% total, 12.1% related). Drug-related TEAEs were reported in 
361 of 654 patients (55.2%) in the Phase 1/2 Monotherapy cohorts; the most frequently reported 
drug-related TEAEs for pirtobrutinib were contusion (12.1%), fatigue (9.6%), and diarrhea 
(8.3%). All other drug-related TEAEs were reported in < 5% of patients (i.e., < 33 patients each). 
TEAEs of severity Grades 3 or 4 were reported in 271 of 654 of patients (41.4%) in the Phase 
1/2 Monotherapy cohorts, with 118 (18.0%) of these Grade 3 or 4 AEs reported as related to 
study drug. On study death (death within 28 days of the last dose of study) due to a Grade 5 
(fatal) TEAE was reported in 25 of 654 patients (3.8%) in the Phase 1/2 Monotherapy cohorts. 
One of the Grade 5 AEs, Enterococcus faecium-related septic shock, was considered to be 
related to study drug; this patient had multiple underlying concomitant risk factors, including 
underlying disease, recent splenectomy prior to enrollment and 11 prior lines of therapy; while 
the Investigator did not deem pirtobrutinib directly causative, study drug was believed to be 
contributory to the event severity.  
In Phase 1b Combination Arms of Study LOXO-BTK-18001, TEAEs were reported in 15 of the 
15 patients (100%) treated in Combination Arm A and in 9 of the 10 patients (90.0%) treated in 
Combination Arm B. The 3 most frequently reported TEAEs in Combination Arm A were 
neutrophil count decreased, nausea, and fatigue (6 patients each [40.0%]). The most frequently 
reported TEAEs in Combination Arm B were constipation, diarrhea, infusion-related reaction, 
and neutrophil count decreased (3 patients each [30.0%]). 
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 60 of 181 
For the most updated information from Study LOXO-BTK-18001, refer to the Investigator’s 
Brochure (Pirtobrutinib IB). Additional updated information about the known and expected risks, 
SAEs, and reasonably anticipated AEs of pirtobrutinib, is also provided in the Pirtobrutinib IB. 
Despite available therapies, pretreated CLL/SLL remains an incurable disease and patients, 
particularly those progressing on targeted therapies, continue to require additional treatment 
especially with novel agents. Thus, there continues to be an unmet need to evaluate new 
therapies in these patients, which the Sponsor will address for this patient population in this 
global Phase 3 study.  
Overall Benefit/Risk Conclusion 
During Phase 1 and 2 studies, pirtobrutinib has demonstrated a tolerable safety profile and a 
durable antitumor activity against a variety of B-cell malignancies, including pretreated 
CLL/SLL. Additionally, considering the measures taken to ensure patient safety in this study, the 
potential risks from taking the study interventions are outweighed by the potential benefits for 
individuals with CLL/SLL. 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 61 of 181 
3. 
OBJECTIVES AND ENDPOINTS 
Table 3.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate progression-free survival (PFS) of 
pirtobrutinib as monotherapy (Arm A) 
compared to Investigator’s choice of idelalisib 
plus rituximab (IdelaR) or bendamustine plus 
rituximab (BR) (Arm B). 
Assessed by Independent Review Committee (IRC): 
PFS per iwCLL 2018 
Secondary 
To evaluate the effectiveness of Arm A 
compared to Arm B based on overall response 
rate (ORR) and time to event(s) outcomes  
Assessed by Investigator:  
PFS per iwCLL 2018 criteria 
Overall survival (OS) 
Time to next treatment (TTNT), defined as time from the date 
of randomization to the date of the next systemic anticancer 
therapy for CLL/SLL (Section 9 for full definition). 
Event free survival (EFS) defined as the time from date of 
randomization to the date of PD or start of new treatment for 
CLL/SLL or discontinuation from treatment due to toxicity or 
death, whichever occurs first. 
Assessed by Investigator and IRC: 
ORR 
Duration of response (DOR) 
To evaluate the safety and tolerability of each 
treatment arm 
Including, but not limited to, serious adverse events (SAEs), 
adverse events (AEs), deaths and clinical laboratory 
abnormalities per National Cancer Institute Common 
Terminology Criteria in Adverse Events v5.0 (NCI CTCAE 
v5.0) 
To evaluate the effectiveness of Arm A 
compared to Arm B based on patient-reported 
outcomes  
Patient-reported outcomes of: 
Time to worsening (TTW) of CLL/SLL-related symptoms 
TTW of physical functioning 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 62 of 181 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
LOXO-BTK-20020 (BRUIN-CLL-321) is a Phase 3 global, randomized, open-label study 
comparing pirtobrutinib as continuous monotherapy (Arm A) to Investigator’s choice of either 
IdelaR or BR (Arm B) in CLL/SLL patients who have been treated with a covalent BTK 
inhibitor, approved (ibrutinib or acalabrutinib) or investigational. The Study Schematic is 
provided in Section 1.2.1. Eligible patients will be randomized in 1:1, Arm A:Arm B, based on 
stratification factors of del 17p presence (yes/no) and receipt of prior venetoclax treatment 
(yes/no).  
BRUIN-CLL-321 will enroll adult CLL/SLL patients with an indication for treatment as defined 
by iwCLL 2018 criteria (Section 10.6, Appendix 6). During Screening, Investigator’s choice 
therapy (IdelaR or BR) must be selected by the Investigator prior to randomization for each 
patient. Patients who have been previously treated with IdelaR or BR and had either 
documented PD as determined by the Investigator, or could not tolerate the regimen, should not 
be retreated with same regimen. Patients assigned to oral pirtobrutinib will receive this 
continuously until discontinuation criteria are met (Section 7). Patients assigned to IdelaR will 
receive rituximab IV for a total of 8 infusion and continuous oral idelalisib until discontinuation 
criteria met (Section 7). Patients assigned to BR will receive up to 6 cycles of both agents 
intravenously and then be followed until progression, death, lost to follow-up or withdrawal of 
consent. Patients randomly assigned to Arm B will be allowed to cross over to Arm A upon 
confirmation of PD by IRC and if they meet the eligibility criteria for crossover (Section 5.3). 
Patients who discontinue treatment for toxicity may still be evaluated for crossover at the time 
of IRC-confirmed PD. Patients who discontinue treatment for any reason other than PD, death, 
lost to follow-up, or withdrawal of consent will be followed for tumor assessment until PD, 
regardless of whether the patient receives a new anticancer therapy.  
4.2. 
Scientific Rationale for Study Design 
This study will compare the efficacy and safety of pirtobrutinib administered as a continuous 
monotherapy with Investigator’s choice of standard-of-care IdelaR or BR. The patient population 
will have received prior BTK inhibitor therapy as part of any number of prior therapies. 
Therefore, the patient population is heterogeneous with regard to treatment exposure and future 
prognosis. The comparator arms for this study are considered to reflect global standard-of-care 
for this patient population. Prior BCL2 inhibitor-based therapy is permitted which will also 
uniquely allow the evaluation of patients who have failed both BTK and BCL2 inhibitor therapy. 
This global study will generate important data characterizing the differences in safety, 
tolerability, and efficacy in this patient population between pirtobrutinib and IdelaR or BR. 
4.3. 
Justification for Dose 
4.3.1. 
Pirtobrutinib 
Preclinical data supporting the selection of the starting dose of pirtobrutinib for the first-in-
human Phase 1/2 study of pirtobrutinib (LOXO-BTK-18001) is provided in the Pirtobrutinib IB. 
During Phase 1 dose escalation, pirtobrutinib has been administered at doses ranging from 
 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 63 of 181 
QD to 300 mg QD. Response was seen at all dose levels including 
 QD and across tumor 
types. PK data obtained during dose escalation demonstrated that at doses of 100 mg QD or 
higher, 
 
 During Phase 1, additional patients were 
enrolled to dose levels cleared for safety to confirm safety and evaluate additional preliminary 
efficacy. In May 2020, based on the totality of PK, safety, and clinical data in Study LOXO-
BTK-18001, the Sponsor and Safety Review Committee (SRC) identified the RP2D of 
pirtobrutinib as 200 mg QD. As of 27 September 2021, 679 patients had been dosed with 
pirtobrutinib in Study LOXO-BTK-18001, and a starting dose of 200 mg QD was administered 
to 569 of the 679 (87.0%) treated patients in the Phase 1/2 monotherapy cohorts, and to all of the 
25 patients treated in Phase 1b combination arms (including 15 patients in Arm A [pirtobrutinib 
plus venetoclax] and 10 patients in Arm B [pirtobrutinib plus rituximab plus venetoclax]). For 
the most updated information from Study LOXO-BTK-18001, refer to the Pirtobrutinib IB.  
4.3.2. 
Idelalisib plus Rituximab 
Idelalisib with rituximab was approved on the basis of a Phase 3 study conducted in previously 
treated CLL patients who were unable to tolerate standard chemoimmunotherapy due to 
co-morbidities, reduced renal function, or persistent myelotoxic effects of prior cytotoxic therapy 
(Furman et al. 2014). In this study, idelalisib was administered orally at 150 mg twice daily 
(BID) dosed continuously and combined with rituximab administered at 375 mg/m2 for the first 
cycle and then 500 mg/m2 on weeks 2, 4, 6, 12, 16, and 20 for a total of 8 doses. As this schedule 
resulted in meaningful clinical activity, idelalisib with rituximab has been approved for use as a 
combination for treatment of patients with relapsed CLL for whom rituximab alone would be 
considered appropriate therapy due to other co-morbidities. The dose and schedule used for 
marketing approval will be used in the IdelaR arm for this study. Dose modification for toxicities 
are detailed in Section 6.6. Premedication may be required for rituximab and should be 
administered per local institutional standard.  
Biosimilar anti-CD20 is permitted in accordance with local prescribing practice. 
Subcutaneous formulation or administration of rituximab is not allowed. Rituximab as IV push 
or bolus administration will not be allowed. Patients should receive the same formulation 
throughout the duration of the trial (either branded or biosimilar). 
4.3.3. 
Bendamustine plus Rituximab 
Bendamustine with rituximab has been administered to patients with r/r CLL with bendamustine 
dosed for 6 cycles at 70 mg/m2 IV on Days 1 and 2 of each cycle and combined with rituximab 
administered at 375 mg/m2 Day 1 of the first cycle and 500 mg/m2 Day 1 of Cycles 2 to 
6 (Fischer et al. 2011). At this dose and schedule, BR results in meaningful clinical activity with 
an ORR rate of 59% and PFS of 15 months in 78 patients evaluated. In this study, Grade 3 
infections occurred in 13% of patients; dose reductions were required in 37% of patients, and 
44% of patients did not receive all 6 cycles of treatment, often due to toxicity. While the 
bendamustine label indicates a monotherapy dose of 100 mg/m2, the bendamustine dose of 
70 mg/m2 has been recommended for use in r/r CLL by the International Consensus Panel 
(Cheson et al. 2016). Thus, the same doses and schedule will be used in the BR comparator 
option for this study. Dose modifications for toxicities are detailed in Section 6.6.  
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 64 of 181 
Premedication may be required for rituximab and should be administered per local institutional 
standard.  
Biosimilar anti-CD20 is permitted in accordance with local prescribing practice. 
Subcutaneous formulation or administration of rituximab is not allowed. Rituximab as IV push 
or bolus administration will not be allowed. Patients should receive the same formulation 
throughout the duration of the trial (either branded or biosimilar). 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the trial globally, which is 
estimated at approximately 
 from the first patient randomized to allow for recruitment 
and follow-up.  
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 65 of 181 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Age 18 or older per local regulations at time of enrollment. 
Type of Patient and Disease Characteristics 
2. Confirmed diagnosis by redacted local laboratory report of CLL/SLL as defined by iwCLL 
2018 criteria, including the following:  
a) B-cells coexpressing the surface antigen CD5 together with at least one B-cell antigen 
(CD19, CD20, CD23) and either  or  light-chain restricted. 
b) ≥ 5 × 109 B lymphocytes/L (5000/µL) in the peripheral blood. For SLL patients, history 
of ≥ 5 × 109 B lymphocytes/L (5000/µL) in the peripheral blood is allowed. 
c) Prolymphocytes may comprise ≤ 55% of blood lymphocytes. 
3. A requirement for therapy consistent with iwCLL 2018 criteria for initiation of therapy such 
that at least 1 of the following should be met: 
a) Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia (such as hemoglobin < 10 g/dL) and/or thrombocytopenia (such as 
platelets ≤ 100 × 109/L). 
b) Massive (i.e., spleen edge ≥ 6 cm below the left costal margin) or progressive or 
symptomatic splenomegaly (≥ 13 cm). 
c) Massive nodes (i.e., ≥ 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy. 
d) Progressive lymphocytosis with an increase of > 50% over a 2-month period or 
lymphocyte doubling time < 6 months. Factors contributing to lymphocytosis other than 
CLL/SLL (e.g., infections, steroid administration) should be excluded. 
e) Autoimmune complications including anemia or thrombocytopenia poorly responsive to 
corticosteroids. 
f) Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine). 
g) Disease-related symptoms (also known as B-symptoms) as deﬁned by any of the 
following: 
i) Unintentional weight loss ≥ 10% within the previous 6 months. 
ii) Signiﬁcant fatigue (i.e., Eastern Cooperative Oncology Group [ECOG] performance 
scale 2 or worse; cannot work or unable to perform usual activities). 
iii) Fevers ≥ 100.5°F or 38.0°C for 2 or more weeks without evidence of infection. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 66 of 181 
iv) Night sweats for ≥ 1 month without evidence of infection. 
4. Known 17p deletion status (wildtype for 17p locus or positive for 17p deletion) by FISH as 
indicated in Section 1.2.2. 
5. Previously treated with a covalent BTK inhibitor, investigational or approved, and either 
alone or in combination with other agents. Patients may have received an unlimited number 
of lines of prior therapy.  
6. Eastern Cooperative Oncology Group (ECOG) 0 to 2. 
7. Must have adequate organ function, as defined below. These values must be met during the 
Screening Period. Results from the most recent assessment during the Screening Period will 
be used for eligibility.  
System 
Laboratory Value 
Adequate Bone Marrow Function (if bone marrow involvement by disease is not present) 
Absolute neutrophil 
count (ANC) 
≥ 0.75 × 109/L without granulocyte-colony-stimulating factor (GCSF) support, or 
≥ 0.50 × 109/L in patients with documented bone marrow involvement considered to 
impair hematopoiesis. GCSF support is permitted in patients with documented bone 
marrow involvement.  
Platelets 
≥ 50 × 109/L. If an Investigator has chosen bendamustine/rituximab as the Arm B 
treatment, platelets must be ≥ 75 × 109/L. Patients may enroll below these thresholds if the 
Investigator determines the cytopenia is related to bone marrow involvement considered 
to impair hematopoiesis. Patients with a platelet count < 30 x 109/L are excluded. 
Hemoglobin 
≥ 8 g/dL, or ≥ 6 g/dL in patients with documented bone marrow involvement considered 
to impair hematopoiesis. Transfusion support is permitted in patients with bone marrow 
involvement.  
Note: Patients who are receiving transfusions of blood or platelets for bone marrow involvement induced 
cytopenias, must be responsive to transfusion support. Patients who are refractory to transfusion support are not 
eligible. If the patient is cytopenic, there should be no evidence of myelodysplastic syndrome or hypoplastic bone 
marrow. 
Hepatic 
Total bilirubin 
≤ 1.5× upper limit of normal (ULN) or if with documented liver involvement ≤ 3× ULN. 
If total bilirubin is > 1.5× ULN the direct and/or indirect (or conjugated/unconjugated 
and/or unconjugated) bilirubin tests should be performed. 
Patients with Gilbert’s Syndrome or hemolysis may be enrolled if indirect (unconjugated) 
bilirubin is < 3× ULN 
(indirect bilirubin = total bilirubin - direct bilirubin) 
Alanine 
aminotransferase 
(ALT) and  
Aspartate 
aminotransferase 
(AST) 
≤ 3.0 × the ULN or with documented liver involvement ≤ 5× ULN 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 67 of 181 
System 
Laboratory Value 
Renal 
Creatinine 
clearance  
≥ 30 mL/minute. If an Investigator has chosen bendamustine/rituximab as the Arm B 
treatment, creatinine clearance must be ≥ (40 mL/minute). 
Using Cockcroft/Gault Formula:  
(140 – age) × body weight (kg) × 0.85 (if female) 
serum creatinine (mg/dL) × 72 
 
8. Patients are required to have had the following washout periods prior to planned C1D1: 
a) Targeted agents or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter 
b) Anticancer therapeutic monoclonal antibodies: 4 weeks; patients who cross over are not 
required to observe this washout period prior to starting crossover treatment. 
c) Palliative limited field radiation: 7 days 
d) Broad field radiation (≥ 30% of bone marrow or whole brain radiotherapy): 28 days 
9. Prior treatment-related AEs must have recovered to Grade ≤ 1, pretreatment baseline, or are 
controlled with medications without meeting other exclusion criteria (with the exception of 
alopecia). 
Contraception  
10. Willingness of men and women of childbearing potential (WOCBP), and their partners, to 
observe barrier and highly effective birth control methods as outlined in Section 10.2 
(Appendix 2 and below) for the duration of treatment and for 6 months following the last 
dose of study treatment or 12 months after the last dose of rituximab, whichever is later.  
WOCBP are defined as those following menarche and who are not postmenopausal 
(or 2 years of non-therapy-induced amenorrhea, or surgically sterile). WOCBP must utilize 
highly effective contraception methods as outlined below. In addition, male partners must use 
a barrier method (condoms) for the duration of treatment and for 6 months following the last 
dose of study treatment or 12 months after the last dose of rituximab, whichever is later. 
Male patients with partners who are WOCBP must use a barrier method (condoms) and their 
partner must also use a highly effective form of contraception as listed below for the duration 
of treatment and for 6 months following the last dose of study treatment or 12 months after 
the last dose of rituximab, whichever is later. 
Highly effective birth control methods with a failure rate of less than 1% per year when 
used consistently and correctly are recommended (Clinical Trial Facilitation Group 
[CTFG 2020]): 
a. Combined estrogen and progestin containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally, or transdermally 
b.  Progestin-only hormonal contraception associated with inhibition of ovulation given 
orally, by injection, or by implant 
c. Intrauterine device (IUD) 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 68 of 181 
d. Intrauterine hormone-releasing system (IUS) 
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence: Considered a highly effective method only if defined as refraining 
from heterosexual intercourse during an entire period of risk associated with the study 
treatment. The reliability of sexual abstinence will be evaluated in relation to the duration 
of the study and to the usual lifestyle of the patient.  
Notes:  
• Women with a history of breast cancer may not use hormone-containing contraception (a, 
b, or d above). One of the other listed methods above should be selected. 
• Women of childbearing potential using hormonal contraception methods should also use 
a barrier method as a second form of contraception. 
• Sperm donation and oocyte donation are prohibited during the duration of participation 
on this protocol and for 6 months after the last dose of study drug, or at least 12 months 
following last dose of rituximab, whichever is later. 
Informed Consent 
11. Willing and capable of giving signed informed consent as described in Section 10.1.2 
Appendix 1 which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. 
Other Inclusions 
12. Able to swallow oral study medication. 
13. Able to comply with outpatient treatment, laboratory monitoring, and required clinic visits 
for the duration of study participation. 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Known or suspected Richter’s transformation to diffuse large B-cell lymphoma (DLBCL), 
prolymphocytic leukemia, or Hodgkin’s lymphoma at any time preceding enrollment. 
2. Known or suspected history of central nervous system (CNS) involvement by CLL/SLL.  
3. Patients who experienced a major bleeding event on a prior BTK inhibitor. 
NOTE: Major bleeding is defined as bleeding having one or more of the following features: 
life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding 
associated with a decrease in the hemoglobin level of at least 2 g/dL; or bleeding in a critical 
area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial 
bleeding or intramuscular bleeding with compartment syndrome) 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 69 of 181 
4. Active second malignancy; patients with treated second malignancy who are in remission 
with life expectancy > 2 years and with documented Sponsor approval are eligible. Examples 
include: 
a) Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without 
current evidence of disease. 
b) Adequately treated cervical carcinoma in situ without current evidence of disease. 
c) Localized (e.g., lymph node negative) breast cancer treated with curative intent with no 
evidence of active disease present for more than 3 years and receiving adjuvant hormonal 
therapy. 
d) Localized prostate cancer undergoing active surveillance. 
e) History of treated and cured Hodgkin's lymphoma or NHL within 5 years from diagnosis. 
5. Major surgery, within 4 weeks of planned start of study treatment. 
6. History of ongoing drug-induced pneumonitis. 
7. Ongoing drug-induced liver injury, primary biliary cirrhosis and/or extrahepatic obstruction 
caused by cholelithiasis, and cirrhosis of the liver. 
8. History of allogeneic or autologous SCT or CAR-T therapy within the past 60 days. 
9. Active uncontrolled autoimmune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], 
idiopathic thrombocytopenic purpura [ITP]) not on a stable regimen and dose for at least 
4 weeks prior to study enrollment. 
10. Significant cardiovascular disease defined as any of the following:  
a) Unstable angina or acute coronary syndrome within the past 2 months prior to 
randomization,  
b) History of myocardial infarction within 3 months prior to randomization,  
c) Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% within the 
12 months prior to randomization, unless subsequent measurements (≥ 2 of any kind, 
separated by a minimum of 3 weeks) documents LVEF recovery > 40%, 
d) ≥ Grade 3 NYHA functional classification system of heart failure, uncontrolled or 
symptomatic arrhythmias 
11. Prolongation of the QT interval corrected (QTc) for heart rate using Fridericia’s Formula 
(QTcF) > 470 msec on 1 Screening ECG.  
a) QTcF is calculated using Fridericia’s Formula (QTcF = QT/(RR^0.33) 
b) Correction of suspected drug-induced QTcF prolongation or prolongation due to 
electrolyte abnormalities can be attempted at the Investigator’s discretion, and only if 
clinically safe to do so with either discontinuation of the offending drug or switch to 
another drug not known to be associated with QTcF prolongation or electrolyte 
supplementation.  
c) Correction of QTc for underlying bundle branch block (BBB) permissible.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 70 of 181 
12. Hepatitis B or hepatitis C testing indicating active/ongoing infection based on Screening 
laboratory tests, defined as:  
a) Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are 
excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative 
HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before 
randomization. Patients who are hepatitis B PCR-positive will be excluded. 
b) Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody 
result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) 
before randomization. Patients who are hepatitis C RNA-positive will be excluded. 
c) For optional crossover, repeat testing is not required. 
13. Known active cytomegalovirus (CMV) infection. Patients with negative status are eligible. 
14. Evidence of other clinically significant uncontrolled condition(s) including, but not limited 
to, uncontrolled systemic infection (viral, bacterial, or fungal) or other clinically significant 
active disease process which in the opinion of the Investigator and Medical Monitor, may 
pose a risk for patient participation. Screening for chronic conditions is not required. 
15. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients 
with unknown or negative status are eligible.  
16. Clinically significant active malabsorption syndrome or other condition likely to affect 
gastrointestinal (GI) absorption of the oral-administered study treatments. 
17. Ongoing inflammatory bowel disease. 
Prior/Concomitant Therapy 
18. Prior exposure to non-covalent (reversible) BTK inhibitor. 
19. Concurrent use of investigational agent or anticancer therapy except hormonal therapy. 
20. Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist. 
21. Use of > 20 mg prednisone QD or equivalent dose of steroid per day at the time of C1D1. 
Patients may not be on prednisone of any dose intended for antineoplastic use. 
22. For patients planned to receive idelalisib: Current treatment with strong cytochrome P450 
(CYP) 3A4 (CYP3A4) inhibitors or inducers (refer to Section 10.4). Because of their effect 
on CYP3A4, use of any of the following within 3 days of use of idelalisib and during study 
treatment is prohibited: 
a) Grapefruit or products from grapefruit  
b) Seville oranges or products from Seville oranges 
c) Star fruit or products from star fruit 
d) Preparations containing St. John’s Wort 
23. Vaccination with a live vaccine within 28 days prior to randomization. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 71 of 181 
Other Exclusions 
24. Pregnancy, lactation, or plan to breastfeed during the study or within 30 days of the last dose 
of study treatment. 
25. Patients with the following hypersensitivity: 
a) Known hypersensitivity, including anaphylaxis, to any component or excipient of 
pirtobrutinib. For patients planned to receive idelalisib, known hypersensitivity, including 
anaphylaxis, to any component or excipient of idelalisib. For patients planned to receive 
bendamustine, known hypersensitivity, including anaphylaxis, to any component or 
excipient of bendamustine.  
b) Prior toxic epidermal necrolysis with any drug, for patients who are planned to receive 
idelalisib 
c) Prior significant hypersensitivity to rituximab requiring discontinuation, prior allergic or 
anaphylactic reaction to rituximab (does not include manageable infusion-related 
reaction)  
d) Known allergy to allopurinol and inability to take uric acid lower agents (i.e., rasburicase 
or febuxostat) 
e) For optional crossover, patients with hypersensitivity to idelalisib, bendamustine, or 
rituximab would not be excluded. 
5.3. 
Eligibility Criteria for Crossover Treatment 
Patients who are randomly assigned to Arm B, may be eligible to cross over to Arm A treatment 
if they meet the following criteria: 
a) IRC-confirmed PD according to iwCLL 2018 (Section 10.6, Appendix 6) 
b) Have not received any other anticancer systemic therapy from the time discontinued the 
control treatment 
c) Patients are required to meet inclusion and exclusion criteria detailed in Sections 5.1 and 
5.2, respectively, to be eligible for crossover to pirtobrutinib, with the exception of 
Inclusion Criterion 8b (i.e., the washout period described in Inclusion Criterion 8b is not 
applicable to patients entering crossover treatment). Given the potential for additive risk 
of serious infection with rituximab and pirtobrutinib, patients should be monitored 
closely for signs and symptoms of infection. 
Once crossover eligibility is confirmed, the Schedule of Assessments for Optional Crossover 
Treatment (for patients crossing over from Arm B to Arm A) (Section 1.3.4) will be 
followed. 
Patients who are eligible for crossover treatment will retain their assigned study number 
during crossover; i.e., patients will NOT be assigned a new study number. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 72 of 181 
5.4. 
Lifestyle Considerations 
5.4.1. 
Meals and Dietary Restrictions 
Patients should refrain from consumption of grapefruit or grapefruit products, Seville oranges or 
Seville orange products, or star fruit or star fruit products from 3 days before the start of 
treatment with idelalisib until after the final dose.  
Other than the previously mentioned fruit and fruit products above, there are no food or drink 
restrictions required for administration of pirtobrutinib or idelalisib.  
Pirtobrutinib or idelalisib tablets should be swallowed whole. 
5.5. 
Screen Failures 
Repeat testing of hematology and/or chemistry tests during the protocol-designated 28-day 
Screening Period is permitted and does not constitute rescreening. Results from the most recently 
repeated hematology and/or chemistry tests during the Screening Period will be used for 
eligibility. 
Screen failures are defined as patients who consent to participate in the clinical study, but are not 
subsequently randomized to a study treatment due to inability to complete or meet the criteria for 
participation (Sections 5.1 and 5.2) during the 28-day Screening Period. Rescreened patients 
must sign a new ICF and will be provided a new patient number with each rescreening. 
Rescreened patients will be required to repeat Screening procedures and tests, with the exception 
of the bone marrow biopsy 
 (if within 90 days of planned randomization) and 
computed tomography (CT)/magnetic resonance imaging (MRI) scan (if within 42 days of 
planned randomization).  
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 73 of 181 
6. 
STUDY INTERVENTION 
6.1. 
Study Interventions Administered 
C1D1 (beginning of treatment administration) should occur within 3 business days after 
randomization, with randomization day being Day 0. 
Table 6.1 
Intervention Groups and Duration 
 
Arm A 
pirtobrutinib 
Arm B  
Investigator’s choice of idelalisib plus rituximab (IdelaR) or  
bendamustine plus rituximab (BR) 
idelalisib plus rituximab (IdelaR) 
bendamustine plus rituximab (BR) 
Treatment 
pirtobrutinib 
idelalisib 
rituximab 
bendamustine 
rituximab 
Dose 
200 mg 
150 mg 
375 mg/m2 on 
C1D1 and then 
500 mg/m2 
70 mg/m2  
375 mg/m2 on 
C1D1 and then 
500 mg/m2 
Schedule 
QD in 
28-day 
continuous 
cycles 
BID in 28-day 
continuous 
cycles 
375 mg/m2 on 
C1D1 and then 
500 mg/m2 Q2W 
for 4 infusions 
and Q4W for 
3 infusions 
70 mg/m2 on Day 
1 and Day 2 of 
each 28-day cycle, 
Cycles 1 to 6 
375 mg/m2 on 
C1D1 and then 
500 mg/m2 
given on Day 1 
of each 28-day 
cycle, Cycles 2 
to 6 
Route 
Oral 
Oral 
IV 
IV 
IV 
Authorized as 
defined by EU 
Clinical Trial 
Regulation 
Not 
authorized 
in EU 
Authorized and 
used according to 
EU authorization 
Authorized and 
used according to 
EU authorization 
Approved in the 
EU and used 
at the dose 
recommended by 
the International 
Consensus Panel 
(see Section 4.3.3) 
Authorized and 
used according to 
EU authorization 
Packaging and Labeling 
Study interventions will be supplied by the Sponsor, or its designee, or by the site, in accordance 
with current Good Manufacturing Practice. Study interventions will be labeled as appropriate for 
country requirements. 
6.1.1. 
Selection and Timing of Doses  
A cycle is defined as an interval of 28 days during treatment period. The 28-day cycle length 
should be maintained throughout the treatment phase regardless of dose interruptions.  
Patients will begin dosing assigned treatment on C1D1 or if crossover, on CO-C1D1. Treatment 
will continue until progression, unacceptable toxicity, or other reason for treatment 
discontinuation. Patients with documented PD as determined by the Investigator may be allowed 
to continue study treatment if the patient is tolerating study drug and, in the opinion of the 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 74 of 181 
Investigator, the patient is deriving clinical benefit from continuing study treatment and 
continuation of treatment is approved by the Sponsor. 
A delay for a maximum of 7 days of a cycle start not due to adverse event, but due to holiday, 
weekend, bad weather, or other unforeseen circumstances, will be permitted and not counted as a 
protocol deviation. Response assessments should remain on the original schedule. 
6.1.2. 
Arm A Pirtobrutinib: General Dosing Instructions  
Each cycle will consist of 28 days. Pirtobrutinib will be given as 200 mg QD administered 
at approximately the same time on each day (refer to Section 6.1). Dosing is intended to be fixed 
(i.e., not weight-based- or body surface area [BSA]-based). 
Study results from a 
 study 
 evaluating the 
 
 of pirtobrutinib showed that 
 
 
 Pirtobrutinib may be taken with food or drink. No fasting is 
required for pirtobrutinib. Refer to Section 6.5 and Section 10.4 (Appendix 4) for concomitant 
medication considerations. 
Patients randomized to pirtobrutinib treatment must keep a daily diary to record dosing 
compliance of oral study treatment, which will also be assessed at each clinic visit by means of a 
tablet count in the returned bottle(s). Late doses (i.e., 4 or more hours after scheduled time) 
should be noted in the diary. Doses that are late by more than 6 hours should not be made up and 
recorded in the dosing diary as missed. Reasons should be recorded for any missed dose. 
Vomiting after dosing should be noted in the diary and a vomited dose should not be re-dosed or 
replaced. Assessment of treatment compliance is described in Section 6.4. 
Patients will continue pirtobrutinib dosing until PD, unacceptable toxicity, or other reason for 
treatment discontinuation. Patients with documented PD as determined by the Investigator may 
be allowed to continue study treatment if the patient is tolerating study drug and, in the opinion 
of the Investigator, the patient is deriving clinical benefit from continuing study treatment and 
continuation of treatment is approved by the Sponsor.  
Effects of pirtobrutinib on coagulation are unknown. Thus, patients undergoing major surgical 
procedures should have pirtobrutinib held at least 3 days prior and 3 days post procedure; the 
Sponsor should be notified of the planned procedure and planned dose hold. 
6.1.3. 
Arm B Investigator’s Choice of IdelaR or BR: General Dosing Instructions 
Patients randomized to Arm B will begin dosing with Investigator’s choice of either IdelaR or 
BR on C1D1, as outlined above in Section 6.1. Refer to local prescribing information for dosing 
and administration details for idelalisib, bendamustine, and rituximab or rituximab’s approved 
biosimilar (US prescribing information is provided for reference: Idelalisib USPI; 
Bendamustine USPI; Rituximab USPI; Rituximab biosimilar Truxima® USPI; Rituximab 
biosimilar Ruxience™ USPI; Rituximab biosimilar Riabni™ USPI). Handling and 
administration of idelalisib, bendamustine and rituximab should be in accordance to instructions 
per locally approved labeling or institutional standards. 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 75 of 181 
Rituximab should only be administered by a healthcare professional with appropriate medical 
support to manage severe infusion reactions that can be fatal if they occur. 
 
Table 6.2 
Specific Instructions for Idelalisib plus Rituximab or Bendamustine plus 
Rituximab 
Investigator’s 
Choice 
Drug 
Administration 
IdelaR 
idelalisib 
• 150 mg dose idelalisib will be administered BID orally until PD or 
unacceptable toxicity 
• Idelalisib may be taken with or without food 
• Tablets should be swallowed whole 
• On days when idelalisib and rituximab are to be administered 
together, idelalisib can be taken any time irrespective of the 
rituximab infusion. 
• Avoid administration of strong CYP3A inducer or substrates with 
idelalisib, and use caution and monitor closely for toxicity with 
CYP3A inhibitors 
• Idelalisib should be prescribed and monitored according to local 
label; this includes monitoring of AST and ALT as summarized in 
Section 8.4.4.10.1, and monitoring of blood counts at least Q2W for 
the first 6 months of idelalisib therapy, and at least weekly in 
patients while neutrophil counts are less than 1.0 Gi/L. Refer to the 
prescribing information of idelalisib for detailed administration and 
safety instructions (Idelalisib USPI). 
rituximaba 
• Rituximab will be infused IV at a dose of 375 mg/m2 on Day 1 of 
the first cycle, followed by 500 mg/m2 Q2W for 4 doses (C1D15, 
C2D1, C2D15, C3D1) and then Q4W for 3 doses (C4D1, C5D1, 
C6D1) for a total of 8 infusions. 
• Rituximab administration by IV push or bolus or subcutaneous 
administration is prohibited. 
• Rituximab should be administered according to local institutional 
standards with appropriate premedications. Refer to the prescribing 
information for rituximab (or for the approved biosimilar that is 
being used) for detailed administration and safety instructions (US 
prescribing information is provided for reference: Rituximab USPI; 
Rituximab biosimilar Truxima® USPI; Rituximab biosimilar 
Ruxience™ USPI; Rituximab biosimilar Riabni™ USPI). 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 76 of 181 
Investigator’s 
Choice 
Drug 
Administration 
BR 
bendamustine 
• Bendamustine will be infused IV at a dose of 70 mg/m2 on Day 1, 
Day 2 of Cycles 1 to 6. 
• On days when rituximab and bendamustine are to be administered, 
rituximab will be administered prior to bendamustine 
• The patient’s BSA calculated at Screening should be used to 
calculate the dose of bendamustine throughout the study unless 
the patient’s weight increases or decreases by > 10% from 
Screening. In obese patients, there is no cap on BSA and actual 
body weight, not adjusted weight, is recommended. Nonetheless, 
empiric dose adjustment is permitted in obese patients (obesity 
defined as body mass index ≥ 30 kg/m2). 
• Refer to the local prescribing information of bendamustine for 
detailed administration and safety instructions (Bendamustine USPI). 
Note that the dose used for this study is 70 mg/m2 (Section 4.3.3). 
• Avoid inducers or inhibitors of CYP1A2. 
rituximaba 
• Rituximab will be infused IV at a dose of 375 mg/m2 on Day 1 of the 
first cycle and 500 mg/m2 on Day 1 of Cycles 2 to 6. 
• On days when rituximab and bendamustine are to be administered, 
rituximab will be administered prior to bendamustine. 
• Rituximab administration by IV push or bolus or subcutaneous 
administration is prohibited. 
• Rituximab should be administered according to local institutional 
standards with appropriate premedications. Refer to the local 
prescribing information for rituximab (or for the approved 
biosimilar that is being used) for detailed administration and safety 
instructions (US prescribing information is provided for reference: 
Rituximab USPI; Rituximab biosimilar Truxima® USPI; Rituximab 
biosimilar Ruxience™ USPI; Rituximab biosimilar Riabni™ USPI). 
a Investigator’s choice of therapy is limited by local approval.  
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Arm A Preparation/Handling/Storage: Pirtobrutinib  
Pirtobrutinib tablets are available at strengths of 
, and 100 mg and will be provided 
to the sites in bottles. The site pharmacist will dispense bottles to the patient in an amount 
necessary to allow for outpatient administration. Tablets are to be stored at room temperature. 
6.2.2. 
Arm B Preparation/Handling/Storage: Investigator’s Choice of IdelaR or BR  
Preparation, storage and handling for idelalisib, rituximab, and bendamustine, will be according 
to instructions provided in the local label for the individual product.  
6.3. 
Measures to Minimize Bias: Randomization  
This is an open-label study. Randomization will be used to minimize bias in the assignment of 
patients to treatment groups, to increase the likelihood that known and unknown patient 
attributes (e.g., demographic and baseline characteristics) are evenly balanced, and to enhance 
the validity of statistical comparisons across treatment groups. 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 77 of 181 
This study will use an interactive voice/web response system (IXRS) for randomization. All 
patients will be centrally assigned to randomized study treatment using IXRS. Patients will be 
randomized 1:1 between Arm A:Arm B, and will be stratified by the status of deletion 17p 
(yes/no) and receipt of prior venetoclax treatment (yes/no).  
If a patient withdraws from the study, then his/her enrollment/randomization code cannot be 
reused. Withdrawn patients will not be replaced. 
6.4. 
Study Intervention Compliance 
For patients randomly assigned to pirtobrutinib or idelalisib treatment, compliance with study 
treatment will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned tablets, and reviewing patient diaries. Deviation(s) from the prescribed dosage 
regimen should be recorded in the electronic case report form (eCRF). 
A patient will be considered noncompliant if he or she takes < 75% of the planned doses of oral 
study drug in a cycle. A patient will also be considered noncompliant if he or she is judged by 
the Investigator to have intentionally or repeatedly taken ≥ 125% of the planned doses of study 
drug over the course of the patient’s treatment.  
Study treatment that is administered by IV will be administered only at the investigational sites 
by the authorized study site personnel. As a result, treatment compliance is ensured. 
6.5. 
Concomitant Therapy 
Concomitant medications will include ongoing medications and all medications that were 
administered within 14 days prior to the planned start of study drug (i.e., from Screening) 
through the Safety Follow-up (SFU) visit (at least 28 days [+7 days] after the last dose of study 
treatment) and are to be recorded in the eCRF. Information regarding reason for use and dates of 
administration including start and end dates should be recorded in eCRF. These concomitant 
medications are to include prescription and nonprescription medications, transfusions, growth 
factor support, vitamins, nutritional supplements, herbal supplements and other remedies. 
Excluded medications for eligibility are indicated in the Exclusion Criteria (Section 5.2). 
6.5.1. 
Allowed Concomitant Medication and Supportive Care 
• Oral contraceptives, hormone-replacement therapy, or other maintenance therapy 
(denosumab, bisphosphonates, and other medications for the treatment of osteoporosis) 
should be continued for the duration of the study. 
• Standard supportive medications must be used in accordance with institutional guidelines and 
Investigator discretion. These may include: 
o Hematopoietic growth factors to treat neutropenia, anemia, or thrombocytopenia in 
accordance with American Society for Clinical Oncology guidelines;  
o Red blood cells (RBCs) and platelet transfusions;  
o Anti-emetic,  
o Analgesic,  
o Antidiarrheal medications; and 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 78 of 181 
o Electrolyte repletion (e.g., calcium and magnesium) to correct low electrolyte levels;  
• Glucocorticoids (≤ 20 mg per day prednisone or equivalent) are allowed preferably for a 
duration of approximately 14 days or less, unless there is a compelling clinical rationale for a 
higher dose or longer duration articulated by the Investigator and approved by the Sponsor. 
Anticipated uses may be short courses to treat asthma or chronic obstructive pulmonary 
disease (COPD).  
• Standard-of-care medications, including hormonal therapy for patients with prostate cancer 
(e.g., gonadotropin-releasing hormone [GnRH] or luteinizing hormone-releasing hormone 
[LHRH] agonists) and breast cancer (e.g., GnRH/LHRH agonists, aromatase inhibitors, 
selective estrogen receptor modulators [SERMs] or degraders [SERDs]), that the patient has 
been receiving for at least 28 days prior to enrollment, are allowed if the disease for which 
the therapy is provided is not a study exclusion or provided they are not on the list of 
prohibited concomitant medications (refer to Section 6.5.2).  
• Local treatment while receiving study treatment (e.g., palliative radiation therapy for 
symptomatic nodal disease) is permitted if the patient is not considered to be clinically or 
radiographically progressing. If the lesion that is to be treated is a target lesion, the lesion 
will be censored at the time of treatment. However, the patient may remain on study provided 
there is other evidence of disease that can be followed for determination of progression. If the 
patient will receive local treatment for symptomatic progression, continuation of therapy post 
progression is allowed as outlined in Section 6.7. 
• Prophylactic antibiotic or IV immunoglobulin (IVIG) therapy for management of patients at 
risk of infections is recommended. Initiation of antibiotic prophylaxis against pneumocystis 
infection (e.g., with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or 
atovaquone) before study drug administration may be warranted, and should be provided for 
patients receiving idelalisib, consistent with the idelalisib USPI. Local practices or guidelines 
regarding infection prophylaxis must be followed. 
• The Sponsor recommends holding pirtobrutinib and bendamustine for at least 3 days before 
and after surgery where bleeding risk cannot be excluded. Any concern for disease flare due 
to a prolonged pirtobrutinib dose interruption should be discussed with the Sponsor, who 
may permit holding pirtobrutinib for a shorter period of time. 
• Premedications before rituximab infusion are anticipated to include 
acetaminophen/paracetamol, antihistamine and /or steroids as per institutional practice. 
For patients on study, steroids used as premedication or as a treatment of an infusion reaction 
may exceed 20 mg of prednisone or equivalent if deemed clinically appropriate by the 
Investigator or if in accordance with institutional practice.  
• The Sponsor recommends that, when medically appropriate and feasible, patients receive 
primary and/or applicable booster SARS-CoV-2 vaccine doses prior to initiating treatment. 
However, clinical judgement and patient autonomy may also guide such decisions. Should a 
patient develop COVID-19 while participating on this clinical trial, the use of potentially 
lifesaving therapy is permitted. This guidance applies to all available oral and IV antiviral 
therapies, as well as to antibody and immunosuppressive treatments that are part of the 
management of patients diagnosed with COVID-19. Ideally, these interventions should not 
be received via enrollment to an additional clinical trial, unless access is otherwise 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 79 of 181 
unavailable. Should a patient receive COVID-19 vaccination or therapy during the study 
period, please follow eCRF instructions for concomitant medication recording for such 
administration.  
6.5.2. 
Prohibited Concomitant Medication 
• Patients receiving idelalisib should not take strong inhibitors or inducers of CYP3A4 (refer to 
Section 10.4) as this could alter the drug’s PK.  
o This restriction includes herbal products, such as St John’s wort, which may decrease the 
drug levels of idelalisib.  
o Patients receiving idelalisib should avoid grapefruit, grapefruit products, Seville oranges, 
Seville orange products, star fruit, and star fruit products, as these contain moderate 
inhibitors of CYP3A. 
o Moderate inhibitors or inducers of CYP3A4 should be taken with caution.  
• Pirtobrutinib inhibits P-gp and is a moderate inhibitor of CYP2C8 and BCRP in the clinic. 
Concomitant use of pirtobrutinib with sensitive P-gp, CYP2C8, or BCRP substrates increases 
their plasma concentrations, which may increase the risk of adverse reactions related to these 
substrates. Recommendations for sensitive P-gp, CYP2C8, or BCRP substrates provided in 
their approved product labeling should be followed (refer to Section 10.4).  
• The coadministration of bendamustine with CYP1A2 inhibitors may increase bendamustine 
plasma concentrations and may result in increased incidence of adverse reactions. Consider 
alternative therapies that are not CYP1A2 inhibitors during treatment with bendamustine.  
• The coadministration of bendamustine with CYP1A2 inducers may decrease bendamustine 
plasma concentrations and may result in decreased efficacy. Consider alternative therapies 
that are not CYP1A2 inducers during treatment with bendamustine. Please refer to local 
labels for bendamustine (US prescribing information provided for reference: 
Bendamustine USPI). Except as indicated in Sections 5.1 and 6.5.1, patients are not allowed 
to receive concomitant systemic anticancer agents, hematopoietic growth factors for 
prophylaxis in Cycle 1, anticancer therapeutic monoclonal antibodies, drugs with 
immunosuppressant properties, or any other investigational agents. No new or alternative 
systemic anticancer therapy is allowed prior to documentation of PD in accordance with 
protocol-specified disease response criteria. 
• Live-virus vaccines should not be given at any time during study treatment, including prior to 
and while receiving rituximab treatment, or during trial participation unless B-cell levels 
have returned to normal.  
• Concurrent administration of idelalisib with other hepatotoxic drugs should be avoided. 
6.5.3. 
Subsequent Anticancer Therapy 
Administration of subsequent anticancer therapy for CLL/SLL is not allowed until:  
• PD any time during treatment as established according to the iwCLL 2018 criteria 
• Withdrawal from study treatment as described in Section 7 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 80 of 181 
After study drug treatment is complete, the following information on subsequent anticancer 
therapies will be collected approximately Q12W after the SFU visit for the first 2 years, and 
approximately Q24W thereafter until death, withdrawal by patient, lost to follow-up, or study 
terminated by Sponsor, whichever comes first:  
• Receipt of all subsequent anticancer therapies 
• iwCLL indication for initiation of subsequent anticancer therapy 
• Response to all subsequent anticancer therapies 
6.6. 
Dose Modification Guidelines  
Dose modifications are allowed for management of study treatment-related toxicities. If dose 
modification of study treatment is required for any AE not related to study treatment, the planned 
dose modification should be reviewed with the Sponsor. Toxicity must resolve to Grade ≤ 1 or 
baseline prior to resuming the next cycle except AEs with no immediate medical consequence 
that can be controlled with adequate treatment (e.g., pain, alopecia, neuropathy, fatigue, nausea, 
vomiting, diarrhea, Grade 2 hypothyroidism, or Grade 2 hypertension). 
Any overdose or incorrect administration of pirtobrutinib, bendamustine, idelalisib or rituximab 
should be noted on the Study Drug Administration eCRF. AEs associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
Regardless of treatment arms, for dose delays, the cycle schedule will be shifted accordingly 
(refer to instructions for data entry in the eCRF guidelines). The protocol schedule of 
radiographic imaging CT/ MRI scans will remain fixed, however. 
For patients in Arm A: Pirtobrutinib may be held for 
 from the last dose to allow 
time to recover from toxicity.  
For patients in Arm B: Initiation of a dose of idelalisib, bendamustine, or rituximab may be 
delayed for a maximum of 28 days to allow a patient sufficient time for recovery from study 
treatment-related toxicity. In exceptional circumstances, a longer delay is permitted upon 
agreement between the Investigator and the Sponsor.  
All dose interruptions and dose modifications and the reasons for those changes will be recorded 
in the eCRF.  
Dose reductions should be made according to the instructions outlined in Sections 6.6.1 and 
6.6.2. 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 81 of 181 
6.6.1. 
Dose Modifications and Toxicity Management Guidelines for Arm A: 
Pirtobrutinib 
Dose hold and/or reduction will be implemented for any patient who experiences a Grade 3 or 
greater non-hematologic toxicity or any patient who experiences any of the clinically significant 
hematologic AEs defined in Table 6.3 (i.e., ≥ Grade 3, or > 1 grade change from baseline if 
baseline is Grade 2 or above) as assessed NCI CTCAE v5.0.  
For each patient, a maximum of 2 dose reductions will be allowed, unless there is a compelling 
clinical rationale for additional dose reduction(s) articulated by the Investigator and approved by 
the Sponsor.  
Table 6.3 
Adverse Events Requiring Dose Modification for Pirtobrutinib  
Adverse Events 
Occurrences 
Requiring 
Dose 
Modification 
ARM A 
(Pirtobrutinib) 
Dose 
Modification 
Instructions 
• Grade 3 or greater 
non-hematologic toxicitya,  
• Grade 3 neutropenia with 
fever and/or infection, 
• Grade 4 neutropenia lasting 
≥ 7 days,  
• Grade 3 thrombocytopenia 
with bleeding, or 
• Grade 4 thrombocytopenia 
First 
occurrence 
No change 
Hold pirtobrutinib until recovery to Grade 1 
or baseline; may restart at original dose level 
(200 mg QD) 
Second 
occurrence 
100 mg QD 
Hold pirtobrutinib until recovery to Grade 1 
or baseline; may restart at one dose level 
lower (100 mg QD)b 
Third 
occurrence 
50 mg QD 
Hold pirtobrutinib until recovery to Grade 1 
or baseline; may restart at one dose level 
lower (50 mg QD) 
Fourth 
occurrence 
Discontinue 
Discontinue  
a For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification 
recommendations should be implemented if patients experience an increase of ≥ 3× baseline AST or ALT, or an 
AST or ALT increase of ≥ 2× baseline with concurrent total bilirubin ≥ 2× ULN.  
b If dose was reduced at first occurrence, reduce by an additional dose level if subsequent events occur. 
If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the 
patient tolerates a reduced dose of pirtobrutinib for ≥ 2 weeks then the dose may be re-escalated 
to the next higher dose level, at the discretion of the Investigator and with written approval of the 
Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as 
outlined. Such re-escalation may be warranted if AE that led to the dose reduction was not 
treatment-related.  
In the event of dosing delays or holds due to toxicity, and subsequent restarting of study drugs, 
the cycle schedule will be shifted accordingly (refer to instructions for data entry in the eCRF 
guidelines). The protocol schedule of radiographic imaging CT/MRI scans will remain fixed, 
however. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 82 of 181 
6.6.2. 
Dose Modification and Toxicity Management Guidelines for Arm B: 
Idelalisib, Rituximab, Bendamustine 
6.6.2.1. 
Dose Modification for Idelalisib 
Refer to the idelalisib local label for dose modification details, and for toxicity management 
guidelines (US prescribing information is provided for reference: Idelalisib USPI). A summary 
of dose modification guidelines from the USPI for idelalisib is provided below and in Table 6.4. 
These serve as a guide and do not replace Investigator judgement and applicable local label 
recommendations if more stringent.  
For other severe or life-threatening toxicities related to idelalisib, withhold drug until toxicity is 
resolved. If resuming idelalisib after interruption for other severe or life-threatening toxicities, 
reduce the dose to 100 mg BID. Recurrence of other severe or life-threatening idelalisib-related 
toxicity upon rechallenge should result in permanent discontinuation of idelalisib.  
In the event of dosing delays or holds due to toxicity, and subsequent restarting of study drugs, 
the cycle schedule will be shifted accordingly (refer to instructions for data entry in the eCRF 
guidelines). The protocol schedule of radiographic imaging CT/MRI scans will remain fixed, 
however. 
If idelalisib is discontinued, patients can continue to receive rituximab up to the maximum 
number of infusions allowed on this protocol. 
Table 6.4 
Recommended Dose Modifications for Idelalisib 
Toxicity 
Dose Modification for Specific Toxicity 
ALT/AST 
> 3-5 × ULN 
> 5-20 × ULN 
> 20 × ULN 
 
Maintain idelalisib 
dose. Monitor at least 
weekly until < 1 × 
ULN 
Withhold idelalisib. 
Monitor at least weekly until 
ALT/AST are < 1 × ULN, then 
may resume idelalisib at 100 mg 
BID 
Discontinue idelalisib 
permanently 
Bilirubin 
> 1.5-3 × ULN 
> 3-10 × ULN 
> 10 × ULN 
 
Maintain idelalisib 
dose. Monitor at least 
weekly until < 1 × 
ULN 
Withhold idelalisib. 
Monitor at least weekly until 
bilirubin is < 1 × ULN, then may 
resume idelalisib at 100 mg BID 
Discontinue idelalisib 
permanently 
Diarrhea* 
Moderate diarrhea 
Severe diarrhea or 
hospitalization 
Life-threatening 
diarrhea 
 
Maintain idelalisib 
dose. Monitor at least 
weekly until resolved 
Withhold idelalisib. 
Monitor at least weekly until 
resolved, then may resume idelalisib 
at 100 mg BID 
Discontinue idelalisib 
permanently 
Pneumonitis 
Any symptomatic pneumonitis 
 
Discontinue idelalisib in patients with any severity of symptomatic pneumonitis 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 83 of 181 
Toxicity 
Dose Modification for Specific Toxicity 
Infections 
Grade 3 or higher sepsis or pneumonia 
 
Interrupt idelalisib until infection has resolved. 
Evidence of CMV infection or viremia 
Interrupt idelalisib in patients with evidence of active CMV infection of any grade or 
viremia (positive PCR or antigen test) until the viremia has resolved. If idelalisib is 
resumed, monitor patients by PCR or antigen test for CMV reactivation at least monthly. 
Evidence of pneumocystis jiroveci pneumonia (PJP) 
Interrupt idelalisib in patients with suspected PJP infection of any grade. Permanently 
discontinue idelalisib if PJP infection is confirmed. 
Intestinal 
Perforation 
Evidence of intestinal perforation 
 
Permanently discontinue idelalisib in patients who experience intestinal perforation. 
Severe Cutaneous 
Reactions 
Suspected/confirmed SJS, TEN, or DRESS, or other severe or life-threatening 
(Grade ≥ 3) cutaneous reactions 
 
Interrupt idelalisib in patients with suspected SJS, TEN, or DRESS until the etiology of 
the reaction has been determined. Permanently discontinue idelalisib in patients with 
confirmed SJS, TEN, or DRESS, or other severe or life-threatening (Grade ≥ 3) cutaneous 
reactions. 
Hypersensitivity 
Reactions 
Evidence of hypersensitivity reactions 
 
Permanently discontinue idelalisib in patients who develop serious hypersensitivity 
reactions. 
Neutropenia 
ANC 1.0 to < 1.5 Gi/L 
ANC 0.5 to < 1.0 Gi/L 
ANC < 0.5 Gi/L 
 
Maintain idelalisib dose 
Maintain idelalisib dose. Monitor 
ANC at least weekly 
Interrupt idelalisib until 
resolution. Monitor 
ANC at least weekly 
until ANC ≥ 0.5 Gi/L, 
then may resume 
idelalisib at 100 mg 
BID 
Thrombocytopenia 
Platelets 50 to < 75 Gi/L 
Platelets 25 to < 50 Gi/L 
Platelets < 25 Gi/L 
 
Maintain idelalisib dose 
Maintain idelalisib dose. Monitor 
platelet counts at least weekly 
Interrupt idelalisib. 
Monitor platelet count 
at least weekly. May 
resume idelalisib at 
100 mg BID when 
platelets ≥ 25 Gi/L 
Note: No dosage modification is recommended for lymphocytosis, which has been observed in some patients 
taking idelalisib. This observed lymphocytosis is a pharmacodynamic effect and should not be considered 
progressive disease in the absence of other clinical findings. 
Source: Zydelig® (idelalisib), United States Prescribing Information (USPI) 
*Moderate diarrhea: increase of 4–6 stools per day over baseline; severe diarrhea: increase of ≥ 7 stools per day 
over baseline. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 84 of 181 
6.6.2.2. 
 Dose Modification for Bendamustine  
Please refer to the bendamustine local label for the current dose modification and toxicity 
management guidelines for bendamustine (US prescribing information provided for reference: 
Bendamustine USPI). The following information provides summary of dose modification from 
the USPI for bendamustine. The conventional criteria for toxicity may be difficult to evaluate 
and require careful consideration of the underlying disease. Dose modifications for hematologic 
toxicity in patients with CLL/SLL should be made with the consideration of an increased 
frequency of abnormal hematologic parameters at baseline.  
If the patient has disease-related splenomegaly or significant bone marrow involvement resulting 
in cytopenia determined to be non-clinically significant, treatment may continue at the 
Investigator’s discretion without dose modification.  
Additional guidance for dose modification of bendamustine is available in the package insert 
(refer to the local label). Bendamustine administration should be delayed in the event of Grade 4 
hematologic toxicity or clinically significant Grade ≥ 2 nonhematologic toxicity. Once 
nonhematologic toxicity has recovered to Grade ≤ 1 and/or the blood counts have improved 
(ANC ≥ 1 × 109/L, platelets ≥ 75 × 109/L), bendamustine can be reinitiated at the discretion of 
the treating physician. In addition, dose reduction may be warranted (refer to Warnings and 
Precautions for Myelosuppression in the local label for bendamustine). 
Bendamustine should be used with caution in patients with mild hepatic impairment. 
Bendamustine should not be used in patients with moderate (AST or ALT 2.5-10× ULN and 
total bilirubin 1.5-3× ULN) or severe (total bilirubin > 3× ULN) hepatic impairment. 
Bendamustine should be used with caution in patients with mild or moderate renal impairment 
and should not be used in patients with creatinine clearance (CrCl) < 40 mL/min. If 
bendamustine is discontinued, patients can continue to receive rituximab up to the maximum 
number of infusions allowed on this protocol. 
Table 6.5 
Dose Modifications for Bendamustine  
Clinically Significant Hematologic Toxicity  
First Reduction 
Reduce the dose to 50 mg/m2 IV on Days 1 and 2 of each cycle 
Second Reduction 
Reduce the dose to 25 mg/m2 IV on Days 1 and 2 of each cycle 
Clinically Significant Non-hematologic Toxicity  
First Reduction 
Reduce the dose to 50 mg/m2 IV on Days 1 and 2 of each cycle 
 
In the event of dosing delays due to toxicity, study treatment dosing of both bendamustine and 
rituximab should be held, and re-administered together once toxicity has resolved to Grade 1 or 
better (or to study baseline).  
In the event of dosing delays or holds due to toxicity, and subsequent restarting of study drugs, 
the cycle schedule will be shifted accordingly (refer to instructions for data entry in the eCRF 
guidelines). The protocol schedule of radiographic imaging CT/MRI scans will remain fixed, 
however. In the event that Day 1 of bendamustine/rituximab of a given cycle is given, and Day 2 
bendamustine is held, the Day 2 bendamustine dose will not be made up.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 85 of 181 
Patients should be asked about symptoms suggestive of infusion-related reactions after their first 
cycle of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be 
asked about symptoms suggestive of infusion reactions after their first cycle of therapy. 
Patients who experienced Grade 3 or worse allergic-type reactions were not typically 
rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and 
corticosteroids should be considered in subsequent cycles in patients who have previously 
experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients 
with Grade 3 or 4 infusion reactions. 
Study drug treatment (both bendamustine and rituximab) may be held a maximum of 
28 consecutive days for a clinically significant toxicity. Study treatment should be discontinued 
in the event of a toxicity lasting > 28 days, unless reviewed and approved by the Sponsor.  
If bendamustine is discontinued, patients can continue to receive rituximab up to the maximum 
number of infusions allowed on this protocol. 
6.6.2.3. 
Dose Modification for Rituximab  
No dose modification is allowed for rituximab, unless it is required to manage infusion-related 
reactions or adverse events. Patients at high risk for infusion-related reactions with rituximab 
may, at the Investigator’s discretion, receive the initial dose of rituximab split over 2 consecutive 
days (C1D1 and Cycle 1 Day 2 [C1D2]). Refer to the rituximab local label (or label for the 
approved biosimilar that is being used) for administration of rituximab (US prescribing 
information is provided as a reference: Rituximab USPI; Rituximab biosimilar Truxima® USPI). 
Rituximab should be administered according to local institutional standards with appropriate 
premedications. 
If rituximab is discontinued, patients can continue to receive idelalisib or bendamustine 
as outlined in this protocol.  
If bendamustine or idelalisib are discontinued, patients can continue to receive rituximab up to 
the maximum number of infusions allowed on this protocol.  
6.7. 
Intervention after the End of the Study 
The end of the study is defined in Section 4.4. Investigators will continue to follow the SoAs 
provided in Section 1.3 until notified by the Sponsor that the end of the study has occurred. 
6.7.1. 
Treatment after Study Completion  
For patients randomized to Arm A: It is anticipated that a patient on this study will receive study 
treatment with pirtobrutinib until the patient is able to obtain commercially available 
pirtobrutinib in their respective country, if the patient does not meet criteria requiring 
discontinuation of treatment, and the patient’s participation in the study has not ended. 
Upon commercial availability in each patient’s respective country, there may be additional 
options for the patient to continue to receive pirtobrutinib once the regulatory requirements are 
satisfied. These may include, but are not limited to 
, patient assistance (should the 
patient qualify), or commercial pirtobrutinib. The study may be terminated if pirtobrutinib does 
not obtain marketing approval or the development of pirtobrutinib is no longer being pursued by 
the Sponsor.  
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 86 of 181 
For patients receiving Arm B: As study drugs used in Arm B are all locally approved and 
marketed, the patients on this study treatment may continue treatment as commercially available 
therapy via physician prescription. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time. 
6.7.2. 
Crossover to Pirtobrutinib 
The SoA for optional crossover treatment (for patients crossing over from Arm B to Arm A) is 
provided in Section 1.3.4. 
6.7.2.1. 
Rationale for Crossover 
Due to the promising benefit/risk profile of pirtobrutinib in Arm A, and the safety profile 
observed to date, patients who are randomized to Arm B may be eligible for crossover to provide 
access to pirtobrutinib while on study, and will continue to be monitored for safety and efficacy. 
Additionally, allowing crossover will provide the opportunity for patients who either completed 
the assigned treatment or discontinued treatment due to toxicity to continue to be followed per 
protocol.  
6.7.2.2. 
Patients who Cross Over upon IRC-Confirmed PD 
The EOT assessment should be completed within 7 days of last dose (date of last dose must be 
recorded in electronic data capture [EDC]) or decision to terminate initial treatment (when 
patient is assigned to treatment and decision to end treatment is made before first dose is taken, 
record the date of end of treatment decision in EDC) as indicated in SoA (Section 1.3.4). 
The SFU assessment is required after the EOT assessment unless crossover C1D1 has occurred 
prior to 28 days after the final dose of Arm B treatment. If crossover C1D1 has occurred prior to 
28 days after the final dose of Arm B treatment, the SFU assessment is not required (i.e., the 
EOT assessment or the CO-C1D1 predose assessment will take the place of the SFU 
assessment). 
6.7.2.3. 
Patients who Complete Bendamustine plus Rituximab Treatment in Arm B or 
Discontinue Treatment in Arm B for Reasons other than PD  
Patients who complete treatment with bendamustine plus rituximab treatment in Arm B or 
discontinue treatment in Arm B for reasons other than PD, but may potentially crossover upon 
IRC-confirmed PD at a later time point, should have the following: 
• The EOT assessment should be completed within 7 days of last dose (date of last dose 
must be recorded) or decision to terminate initial treatment (when patient is assigned to 
treatment and decision to end treatment is made before first dose is taken, record the date 
of end of treatment decision) as indicated in SoA (Section 1.3.4).  
• The SFU assessment should follow the EOT assessment, unless crossover C1D1 has 
occurred prior to 28 days after the final dose of Arm B treatment, in which case the EOT 
assessment or CO-C1D1 predose assessment will take the place of the SFU assessment.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 87 of 181 
• LTFU assessment and procedures will be conducted in accordance with SoAs in 
Section 1.3.2 or Section 1.3.3.  
• Crossover Screening assessments should be conducted within 42 days of IRC-confirmed 
PD, as indicated in SoA (Section 1.3.4). 
6.7.3. 
End of Treatment 
Patients who discontinue treatment for reasons other than PD should remain on study and 
continue to have disease assessments performed per protocol as part of LTFU (refer to 
Section 6.7.5; patients who cross over are discussed in Section 6.7.2). For all study treatments, 
the EOT assessments and procedures will be conducted in accordance with the SoAs 
(Section 1.3).  
Patients receiving BR who discontinue from the study treatment for reasons other than PD and 
before completion of the planned 6 cycles of therapy should remain on study and continue to 
have disease assessments performed per protocol as follow-up for progression and survival. For 
all patients treated with BR, whether discontinuing prematurely or at the completion of 6 cycles 
of therapy, an EOT assessment should occur within 7 days of last dose of study treatment or 
decisions to terminate study treatment. Patients will have a separate SFU visit to determine the 
status of any unresolved AEs (Section 6.7.4). 
6.7.4. 
Safety Follow-up  
The SFU assessments will be conducted in accordance with the SoAs (Section 1.3). Safety 
follow-up procedures may be performed as part of the EOT visit if the latter was performed 
28 days (+ 7 days) after final dose of the last cycle.  
For patients on continuous pirtobrutinib or idelalisib (for IdelaR), at the decision to discontinue 
study treatment, the EOT visit is required within 7 days of stopping treatment. A SFU visit 
28 days (+ 7 days) after the EOT visit should be performed if EOT occurred for AEs to 
determine the status of any unresolved AEs. 
For patients who cross over to Arm A from Arm B, the SFU visit is not required if Arm A 
treatment is initiated less than 28 days after the final dose of Arm B treatment (i.e., the EOT 
assessment or the CO-C1D1 predose assessment will take the place of the SFU assessment). 
6.7.5. 
Long-Term Follow-up 
The LTFU assessments and procedures will be conducted in accordance with the SoAs 
(Section 1.3). After treatment discontinuation, LTFU will occur approximately Q12W 
(± 4 weeks) for up to 2 years and Q24W (± 4 weeks) thereafter, until the patient withdraws 
consent for further participation, is lost to follow-up, has died, or close of the study. If a patient 
discontinues study treatment for reasons other than PD, death, lost to follow-up, or withdrawal of 
consent, the patient will be followed for disease assessment at regular intervals until PD by 
imaging as specified in Section 10.6 (Appendix 6) utilizing the same modality(ies) used for the 
baseline imaging assessment. In addition to monitoring for progression, assessments may include 
subsequent anticancer therapy(ies) and survival status. Investigators should follow up and report 
occurrence of a second primary malignancy (SPM) for up to 5 years from the start of study 
treatment (refer to Section 8.5.8). 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 88 of 181 
LTFU may be conducted by telephone when response assessment is not scheduled. Unscheduled 
interactions which may also constitute a long-term follow-up assessment can be reported in the 
appropriate eCRF.  
For any patient who is lost to follow-up, the study site will attempt to ascertain survival 
information via public database search. If survival status still cannot be ascertained, patients will 
be considered lost to follow-up and will be censored appropriately.  
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 89 of 181 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PATIENT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention  
Patients will be advised that they are free to discontinue study treatment at any time and that they 
will be followed for survival after discontinuing treatment (refer to SoAs in Section 1.3, and to 
Section 6.7.5). Over the course of the study, the Investigator and/or the Sponsor should 
discontinue a patient from treatment for any of the reasons listed below: 
• PD per iwCLL 2018 criteria 
Exception: Patients with documented PD who are tolerating treatment, are deriving clinical 
benefit from continuing study treatment in the opinion of the Investigator, and who are likely 
to experience a worse outcome with discontinuing rather than continuing therapy at the time 
of progression (e.g., no remaining treatment options with known benefit), may continue 
treatment with prior Sponsor approval. Arm B patients who continue study treatment beyond 
IRC-confirmed progression are not eligible for crossover. 
• Unacceptable toxicity 
• Intercurrent illness compromising ability to fulfill protocol requirements 
• The patient becomes pregnant during the study 
• Requirement for alternative treatment in the opinion of the Investigator, unless such 
treatment is temporary (e.g., local radiation or surgery needed to palliate symptoms of the 
disease that does not otherwise meet the definition of PD) 
• If receiving pirtobrutinib, dose delay 
 for hematologic toxicity, unless a clinical 
need for prolonged delay has been determined by the Investigator with documented Sponsor 
approval. For Arm B patients with dose delay > 28 days for unacceptable toxicity, consult 
product package insert. 
• Patient is noncompliant, with study procedures and/or treatment upon review with 
the Sponsor 
• Any medical condition that the Investigator determines to be a clinically significant finding 
which is identified after enrollment and which may jeopardize the patient’s safety if study 
treatment is continued. 
• Withdrawal of consent  
• Investigator decides that the patient should be discontinued from study treatment.  
• Lost to follow-up 
• Death 
• Study terminated by Sponsor 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 90 of 181 
At the time a patient discontinues treatment, all safety data normally required at the EOT visit 
will be obtained if possible, as outlined in Section 6.7.3. Patients will enter LTFU where they 
may be required to undergo disease assessments (refer to Section 6.7.4). Patients who 
discontinue on Arm B may be considered for crossover to Arm A as determined by eligibility 
(refer to Section 5.3). 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
Patients will be discontinued under the following circumstances 
• Participation in the study needs to be stopped for medical, safety, regulatory, compliance or 
other reasons consistent with applicable laws, regulations, and GCP 
• Death 
• Patient is lost to follow-up 
• Patient or patient’s designee withdraws consent 
• Study terminated by the Sponsor 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the Investigator must document this in the site study records.  
7.2.1. 
Discontinuation of Inadvertently Enrolled Patients 
If the Sponsor or Investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, the Sponsor and Investigator will determine if it is medically appropriate 
to continue. The Investigator must obtain documented approval from the Sponsor to allow the 
inadvertently enrolled patient to continue in the study. 
Patients will adhere to the protocol-specified assessments including SFU which is as outlined in 
the SoAs (Section 1.3), Section 8.5 (Adverse Events and Serious Adverse Events), and 
Section 8.4 (Safety Assessments). 
7.3. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel are expected to make diligent 
attempts to contact patients who fail to return for a scheduled visit or were otherwise unable to 
be followed up by the site. 
Discontinuation of specific sites or of the study as a whole is described in Section 10.1.11.2. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 91 of 181 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoAs. Protocol waivers or exemptions 
are not allowed. Immediate safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the patient should continue or discontinue study 
treatment. Adherence to the study design requirements, including those specified in the SoAs, is 
essential and required for study conduct. 
8.1. 
Screening 
All Screening evaluations must be completed and reviewed by the appropriate site personnel to 
confirm that potential patients meet all eligibility criteria.  
The Investigator will maintain a Screening log to record details of all patients screened and to 
confirm eligibility or record reasons for Screening failure, as applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood counts, 
scans) and obtained before signing of the ICF may be utilized for Screening or baseline purposes, 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoAs (Section 1.3). 
Screening results within 3 days of C1D1 are acceptable as C1D1 results. 
8.2. 
Medical History 
Patient complete medical history should include disease-related signs and symptoms, initial date 
of CLL/SLL diagnosis, Rai stage, and prior CLL/SLL-related therapies should be documented 
including regimen, duration and response to prior therapies when available.  
Any disease-related complications including immune-mediated complications (immune-
mediated thrombocytopenia or hemolysis) should be recorded if data is available.  
8.3. 
Efficacy Assessments 
8.3.1. 
Response Assessment  
Response will be assessed by the Investigator and the IRC based on physical examination, 
imaging, hematology results and bone marrow examinations as described using the iwCLL 2018 
response criteria which will include partial remission with lymphocytosis (PR-L), 
complete remission with an incomplete marrow recovery (CRi) and nodular partial remission 
(nPR) (Hallek et al. 2018, Cheson et al. 2012; Section 10.6, Appendix 6). A central radiology 
vendor will be used to collect images for IRC review. All patients must have clinical 
examinations and response assessments during the course of treatment, while on study, and 
during follow-up as indicated in the SoAs (Section 1.3).  
With approved BTK inhibitors, lymphocytosis and leukocytosis are well-documented on-target 
effects that occur early during administration of study treatment. These reactions are not 
reflective of PD in the absence of other signs of PD (e.g., splenomegaly, enlarging lymph nodes, 
disease-related constitutional symptoms) and will not be considered PD. Guidance for recording 
of disease-related symptoms is provided in Section 8.4.2.1. 
All measurable disease must be documented at Screening and reassessed at scheduled timepoints 
indicated in the SoAs (Section 1.3).  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 92 of 181 
Radiologic disease assessment will be conducted by the Investigator in accordance with the 
SoAs (Section 1.3) and the Imaging Manual. Investigators should use the same method 
consistently for an individual patient throughout the study. Both CLL and SLL responses will 
be assessed per iwCLL 2018 criteria (Section 10.6, Appendix 6). Target lesions must be nodal 
lesions (lymph nodes) ≥ 1.5 cm. CT scan with IV contrast agent is the preferred method of 
assessment with scans of neck, chest, abdomen, and pelvis. However, MRI is acceptable if 
CT scan with contrast agent is contraindicated (refer to Imaging Manual for detailed 
instructions). 
For patients with documented disease involving blood/bone marrow, but with no documented 
baseline radiographic findings and thus where radiology is not required for routine response 
assessment, imaging is to be performed Q24W according to the SoAs (Section 1.3).  
If patient terminates treatment prior to a scheduled response assessment, the patient should have 
that response assessment done at the EOT visit. This assessment does not need to be repeated if 
performed within 2 weeks prior to the EOT visit, or if tumor progression was previously 
determined. 
A bone marrow 
 biopsy should be collected during Screening and for confirmation of 
CR per the SoAs (Section 1.3), and submitted for central assessment. Refer to Section 8.9.1. 
Guidance on sample collection and timing is provided in the Laboratory Manual. 
According to iwCLL 2018, diagnosis of Richter’s transformation is established by biopsy of the 
affected site (not required for this study). However, if per local standard-of-care or at 
Investigator discretion, an ancillary whole PET-CT scan (not required for study) is performed, 
the results of this scan should be captured in the EDC as directed in the CRF Completion 
Guidelines. 
8.3.1.1. 
COVID-19 Vaccination and Response Assessment 
COVID-19 vaccination has been shown to cause transient, reactive adenopathy in approximately 
10% of patients. Typically enlarged axillary, cervical, and supraclavicular lymph nodes in the 
vicinity of the drainage area of the injection site have been observed transiently 
(Herishanu et al. 2021; Lehman et al. 2021; Tu et al. 2021). Such transient enlargement of lymph 
nodes may resemble PD, and therefore, may confound interpretation of response assessment. 
Although response assessment should be performed according to the SoAs (Section 1.3), the 
following recommendations should be considered for potential COVID-19 vaccination patients: 
• If a COVID-19 vaccine is scheduled around the same time as an imaging visit for this study, 
it is preferable that if scheduling permits, the scans should be done before the COVID-19 
vaccination.  
• If a vaccination has already occurred near the imaging visit, the imaging schedule should 
continue to be followed, without delaying patient care.  
• If adenopathy is observed in the vicinity of the drainage area of the COVID-19 vaccination 
injection site, a follow-up scan after 6 to 8 weeks should be considered as this adenopathy 
should be transient and should resolve in this time period. 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 93 of 181 
8.3.2. 
IRC Assessment 
Response assessments will be assessed by the IRC. Disease assessment (including scans and 
other disease assessments) will continue until IRC-confirmed PD. These data will constitute the 
primary assessment for PFS analysis, following IRC review. All scans, regardless of patient 
treatment status should be sent for IRC review, except for scans from patients in crossover arm. 
Prior to crossover from Arm B to Arm A (Section 6.7.2), a patient may continue treatment and 
remain under close observation until progression is confirmed by the IRC. 
8.4. 
Safety Assessments 
8.4.1. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) will be assessed after the patient has rested in the sitting position. 
8.4.2. 
Physical Examination 
The Screening physical examination will include, at a minimum, the general appearance of the 
patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, 
lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic 
system.  
Symptom-directed physical exams will be done during the treatment period, at the EOT and SFU 
visits, and during the post-treatment disease follow-up.  
8.4.2.1. 
Disease-Related Symptoms 
Disease-related symptoms will be assessed and recorded in the patient records and are defined 
per Hallek 2018 as:  
a) Unintentional weight loss of 10% of more within the previous 6 months;  
b) Significant fatigue (i.e., ECOG PS 2 or worse; inability to work or perform usual 
activities); 
c) Fevers higher than 100.5°F or 38°C for 2 or more weeks without other evidence of 
infection; or  
d) Night sweats for more than 1 month without evidence of infection  
8.4.3. 
Electrocardiograms 
ECG monitoring should be performed in accordance with the SoA for the treatment arm (Arm A 
SoA in Section 1.3.1; Arm B SoAs in Sections 1.3.2 and 1.3.3; Crossover SoA in Section 1.3.4). 
To minimize variability, it is important that patients are in a resting position for at least 5 minutes 
prior to ECG evaluation. Body position should be consistently maintained for each ECG to 
prevent changes in heart rate. ECGs for each patient should be obtained from the same machine 
whenever possible. Any clinically significant changes in ECGs that occur during the study 
should be reported as an AE in the eCRF which will also collect pertinent clinical information. 
Loxo may request de-identified copies of the ECGs for adjudication. Sites are required to submit 
ECG tracings for Sponsor review in these circumstances. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 94 of 181 
• Manually review ECGs to confirm accuracy. ECGs must be interpreted by a qualified 
physician (the Investigator or qualified designee) at the site for immediate patient 
management. 
• If the ECG is abnormal,  
o Assess for all possible causes (concomitant medications, electrolyte abnormalities, 
underlying cardiac conditions, etc.). 
o Clinical chemistry should be assessed and if electrolytes are abnormal, they should be 
repeated as indicated. Potassium should be ≥ 4 meq/L and less than ULN and magnesium 
and calcium should be within normal limits. 
o Serial repeat ECG collection to ensure resolution should be conducted as clinically 
appropriate. 
• If patients have an underlying BBB, ECGs must be manually reviewed by a qualified 
physician and the QTc value must be corrected (utilizing locally approved correction factors 
or based upon guidance provided in Section 10.7, Appendix 7) and this value should be 
entered into the eCRF. 
• If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing. 
• If triplicate ECGs are obtained to confirm a Grade 3 AE (QTcF ≥ 501 msec) as outlined in 
the NCI CTCAE v5.0 criteria, ECGs should be collected preferably 1-minute apart, and the 
cumulative collection time for all 3 ECGs should not exceed 5 minutes. 
• Patients should be clinically monitored for symptoms of cardiac arrhythmias 
(e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. ECG should 
be done as clinically indicated for assessment with electrolyte panel. If a clinically significant 
arrhythmia is discovered (e.g., atrial fibrillation/atrial flutter), the clinical circumstances 
surrounding the time of onset (if known; e.g., time/date of onset, activity and/or lifestyle 
changes/factors at the time of onset, associated symptoms, laboratory values) must be 
documented in the eCRF and study required documents and provided as requested by the 
Sponsor. 
8.4.4. 
Clinical Safety Laboratory Assessments 
All protocol-required laboratory assessments must be conducted in accordance with the 
Laboratory Manual and the SoAs (Section 1.3). Sites with documentation specifying certain 
analytes or procedures are not collected per site policy or local regulation will not be considered 
protocol deviations if Sponsor approval is granted.  
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected for the 
patient's condition. Clinically significant laboratory results should be reported as AEs 
(AE section of the eCRF) if the results require a change of study treatment or require medical 
intervention.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant abnormalities occurring during the study. 
• The laboratory reports must be filed with the source documents.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 95 of 181 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of study treatment should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator. 
○ If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, additional etiologies should be identified and reported as an AE as 
appropriate. 
○ If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in patient management or are 
considered clinically significant by the Investigator especially if resulting in study 
treatment management (e.g., dose modification), reporting of the abnormality (e.g., AE 
or SAE) should be performed and recorded in the eCRF. 
Local laboratories will be utilized for routine laboratory tests and SFU (e.g., blood chemistries 
from serum or plasma, hematology, and urinalysis). Special assessments will be performed 
centrally, including hematology tests associated with IRC assessment of response and 
 
. Additional guidance regarding testing and handling and processing of samples for 
central assessment is provided in the Laboratory Manual. 
8.4.4.1. 
Hematology 
Hematology should be assessed locally in accordance with the SoAs (Section 1.3). In addition, at 
each response assessment, a sample is required to be submitted centrally, as a component of the 
IRC assessment of disease response. Patients on crossover will be assessed locally by the 
Investigator. Hematology assessments will include: hemoglobin, hematocrit, RBC count, white 
blood cell (WBC) count, platelet count, percent or absolute differential (neutrophils, 
lymphocytes, eosinophils, basophils, and monocytes). 
8.4.4.2. 
Blood Chemistry 
Blood chemistry from serum or plasma should be assessed locally in accordance with the SoAs 
(Section 1.3) and should include assessment of the following: sodium, potassium, chloride, 
glucose, creatinine, total protein, albumin, total bilirubin, ALT, AST. Alkaline phosphatase can 
be performed as needed. Direct (or indirect) bilirubin should be performed at any time total 
bilirubin is abnormal. As indicated in the SoA, lactate dehydrogenase (LDH), calcium, 
magnesium, phosphorus and uric acid are required at Screening and D1 of each Cycle 1 to 6.  
If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, 
and potassium) should be done to coincide with the ECG testing if clinically feasible (this is also 
noted in ECG instructions on each SoA in Section 1.3). 
8.4.4.3. 
Beta-2 Microglobulin 
Beta-2 microglobulin test should be assessed locally in accordance with the SoAs (Section 1.3). 
8.4.4.4. 
Serum Immunoglobulins 
Local assessment of serum immunoglobulins includes IgG, IgM and IgA levels. 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 96 of 181 
8.4.4.5. 
CMV Testing 
Local CMV testing at Screening must include serologic testing for CMV IgG, IgM and 
deoxyribonucleic acid (DNA) PCR testing. Patients receiving idelalisib should be monitored 
every 3 months in accordance with the SoA (Section 1.3.2) with local CMV DNA PCR testing. 
8.4.4.6. 
Coagulation 
The coagulation panel should include activated partial thromboplastin time (aPTT) and 
prothrombin time (PT) or international normalized ratio (INR) and should be assessed locally. 
8.4.4.7. 
Urinalysis 
Urinalysis that includes color, specific gravity, pH, glucose, bilirubin, occult blood, protein, 
leukocytes, and urobilinogen should be assessed locally in accordance with the SoAs 
(Section 1.3). 
8.4.4.8. 
Pregnancy Testing 
For women of childbearing potential (WOCBP): Pregnancy testing (serum or urine) must be 
conducted at Screening and as outlined in the SoAs (Section 1.3) or as required per local 
regulations and/or institutional guidelines and may be performed locally. Pregnancy reporting 
guidance is provided in Section 8.5.7. All WOCBP, defined as women who are following 
menarche and who are not postmenopausal (or 2 years of non-therapy-induced amenorrhea) or 
surgically sterile will have a serum or urine pregnancy test at Screening. If any urine pregnancy 
test is positive, study treatment will be delayed until the patient pregnancy status is confirmed by 
a serum pregnancy test. If serum pregnancy test is positive, the patient will be permanently 
discontinued from study treatment. 
8.4.4.9. 
Viral Testing 
Hepatitis testing should be assessed at Screening in accordance with the SoA (Section 1.3) and 
should include testing for hepatitis B (hepatitis B surface antigen [HBsAg], hepatitis B surface 
antibody [HBsAb], and total hepatitis B core antibody [HBcAb]) and hepatitis C virus (HCV) 
antibody serology. Screening for CMV includes IgM, IgG and CMV DNA by PCR. Follow-up 
testing will be performed as indicated clinically, or Q12W in patients receiving IdelaR. If other 
testing indicates acute or chronic infection or reactivation of infection, obtain viral load (e.g., 
quantitative hepatitis B virus [HBV]-DNA, HCV-RNA). Patients with evidence of active 
hepatitis B and/or hepatitis C infection (as defined in the exclusion criteria) are excluded from 
participation in the trial.  
Patients with known active CMV infection and/or a history of positive HIV test (regardless of 
CD4 count) are excluded from participation in the trial due to potential drug-drug interactions 
between antiretroviral medications and pirtobrutinib and risk of opportunistic infections with 
both HIV and approved BTK inhibitors.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 97 of 181 
8.4.4.10. Hepatic Safety Monitoring 
Hepatic laboratory work-up outlined in Section 10.3 (Appendix 3) should be collected in the 
event that a patient experiences elevated AST/ALT and bilirubin meeting the following criteria, 
at any time from Screening through EOT:  
• AST or ALT > 3× ULN with total bilirubin 2× ULN  
Hepatic safety monitoring should be performed in accordance with local label for the individual 
product. 
For patients enrolled with abnormal liver function at baseline (AST and/or ALT ≥ 1.5× ULN at 
baseline), a dose interruption should be implemented (as indicated in Table 6.3) if the AST or 
ALT ≥ 3× baseline or AST or ALT ≥ 2× baseline with concurrent total bilirubin ≥ 2× ULN, until 
liver function returns to baseline. If the abnormality persists or worsens, further clinical and 
laboratory monitoring and evaluation, for possible causes of abnormal liver tests, should be 
initiated by the Investigator and possibly in collaboration with a hepatobiliary consultation as 
clinically appropriate. At a minimum, this evaluation should include a physical exam, a thorough 
medical history (including symptoms and recent illness), history of concomitant medications 
(including over the counter and herbal preparations and dietary supplements), and history of drug 
and alcohol use. In addition, a blood test for PT-INR and abdominal imaging studies (e.g., 
ultrasound) should be obtained. Additional laboratory examinations (including, for example, 
serological tests for viral hepatitis A, B, C, E) should also be considered.  
For patients who are anti-HBc positive at Screening, it is advised to monitor HBV DNA levels 
closely during treatment (every 1-3 months) through 6 months after discontinuation. If HBV 
DNA becomes detectable, it is advised to consider discontinuation of study drug and to consult a 
hepatologist (for further assessment and treatment), and to communicate with the Sponsor. 
8.4.4.10.1. Hepatic Safety Monitoring: Idelalisib 
For patients receiving idelalisib, monitor hepatic function according to the local label: 
• Monitor ALT and AST in all patients Q2W for the first 3 months of treatment 
• Monitor ALT and AST Q4W for the next 3 months 
• Monitor ALT and AST every 1 to 3 months thereafter 
• If the ALT or AST rises above 3× the ULN: Monitor AST and ALT weekly for liver 
toxicity until resolved 
• If the ALT or AST is greater than 5× the ULN: Withhold idelalisib and continue to 
monitor AST, ALT and total bilirubin weekly until the abnormality is resolved 
In the event of transaminase elevation, refer to Section 6.6.2.1 for the summary table of 
recommended dose modifications for idelalisib, or refer to idelalisib local label for dose 
modification details. The concurrent administration of idelalisib with other hepatotoxic drugs 
should be avoided. 
8.4.4.10.2. Hepatic Safety Monitoring: Rituximab 
For patients who are anti-HBc-positive at Screening, it is advised to monitor HBV DNA levels 
closely during treatment (every 1-3 months) through 6 months after discontinuation. If HBV 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 98 of 181 
DNA becomes detectable, it is advised to consider discontinuation of study drug and to consult a 
hepatologist (for further assessment and treatment), and to communicate with the Sponsor. 
8.5. 
Adverse Events and Serious Adverse Events and Other Safety 
Reporting 
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting the Sponsor or its designee of any event that seems unusual, even if this 
event may be considered an unanticipated benefit to the participant. The Investigator is 
responsible for the appropriate medical care of participants during the study and must document 
their review of each safety report. 
8.5.1. 
Definitions 
8.5.1.1. 
Adverse Events 
An AE is any unfavorable medical occurrence in a patient administered an investigational 
product, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of the investigational product, whether or not considered related to the 
investigational product.  
All AEs that occur prior to the first dose are considered medical history and will be recorded as 
such in the eCRF unless the AE develops or worsens due to study-related procedures.  
Documentation must be supported by an entry in the patient’s source medical records. 
Laboratory test abnormalities considered by the Investigator to be clinically relevant should be 
reported in the eCRF as an AE. Each AE is to be evaluated for duration, severity, and causal 
relationship with the investigational product or other factors.  
Disease progression of the primary tumor in and of itself is captured as an efficacy assessment 
and should not be captured as an AE (including fatal AEs). If toxicities due to PD exist, and are 
new or worsened from baseline, these should be reported as AEs. If a new primary malignancy 
appears, it will also be considered an AE. 
Lymphocytosis associated with BTK inhibitor treatment is a well-documented on-target effect 
and should only be considered an AE if clinically significant.  
An overdose in and of itself is not considered an adverse event. However, if a patient who 
experiences an overdose has signs and symptoms that meet any AE or SAE criterion, this must 
be reported in the appropriate manner and timeframe and must be documented as clinical 
sequelae of an overdose. The Sponsor should be notified of any overdose, accidental or 
otherwise, and should be provided confirmation that no adverse event was experienced as a 
result. Refer to Section 8.6. 
A DMC will be established to oversee the safety aspects of the study. Refer to Section 9.6. 
The event term of ‘death’ itself should not be reported as an AE; rather, any AEs associated with 
the occurrence of death or AEs considered to be Grade 5 in severity (fatal) should be reported. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 99 of 181 
8.5.1.2. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that, at any dose: 
• results in death 
• is life-threatening 
• requires hospitalization or prolongation of existing hospitalization  
• results in disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event 
Medical or scientific judgement should be exercised in deciding whether reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the patient or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition. These 
events should also be considered serious. 
Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. However, if institutional guidelines mandate hospitalization for a planned 
procedure (e.g., transfusion of blood products, such as packed red blood cells (PRBCs), platelets 
or plasma), the underlying AE requiring intervention should not be reported as an SAE unless it 
meets other serious criteria. An emergency room visit without hospital admission will not be 
recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled or 
planned.  
Unexpected complications and/or prolongation of hospitalization that occur during elective 
surgery should be recorded as AEs and assessed for seriousness. Admission to the hospital for 
social or situational reasons (i.e., no place to stay, live too far away to come for hospital visits) 
will not be considered inpatient hospitalizations. 
8.5.2. 
Grading and Intensity of Adverse Events 
The Investigator will grade the severity of each AE using, when applicable, the NCI CTCAE, 
v5.0. In the event of an AE for which no grading scale exists, the Investigator will classify the 
AE as mild, moderate, severe, life-threatening/debilitating, or fatal, as defined below.  
• Grade 1 mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• Grade 2 moderate; minimal, local or non-invasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL). 
• Grade 3 severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• Grade 4 life-threatening* consequences; urgent intervention indicated. 
• Grade 5 death related to AE. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 100 of 181 
*Life-threatening: an AE that places the patient at immediate risk of death. It does not include an 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
Laboratory values which meet Grade 4 NCI CTCAE v5.0 severity based on numeric value may 
not necessarily meet life-threatening criteria. 
8.5.3. 
Relationship to Underlying Disease, Other Medical Condition or 
Concomitant Medications 
The Investigator will categorize each AE as to its potential relationship to underlying disease, 
other medical conditions or concomitant medications using the categories of Yes (causally 
related) and No (not related) as described in Section 8.5.2 and defined below. The assessment of 
the relationship of an AE to the underlying disease, other medical conditions, or concomitant 
medications is a clinical decision based on all available information at the time. 
No: 
The time course between the occurrence or worsening of the AE and underlying disease, other 
medical conditions, or concomitant medications indicates an alternative causal relationship 
(other than study drug) and another cause is considered more likely. 
Yes: 
The time course between the occurrence or worsening of the AE and the underlying disease, 
other medical conditions, or concomitant medications is consistent with a causal relationship to 
study drug and another cause is considered unlikely. 
The following factors should also be considered: 
• Temporal sequence from treatment with the study drug. 
• Preclinical and prior clinical data regarding whether a particular AE could be an effect of the 
study drug (or class of drug). 
• Pharmacology and PK of the investigational product. 
An unexpected AE is an experience not previously reported or an AE that occurs with 
specificity, severity, or frequency that is not consistent with the current Pirtobrutinib IB or local 
labels for idelalisib, rituximab or bendamustine. For contraindications for idelalisib, 
bendamustine, and rituximab or rituximab’s approved biosimilar, refer to local prescribing 
information. 
8.5.4. 
Adverse Event Reporting 
The Sponsor or its representative is required to report certain study events in an expedited 
manner to the FDA, the European Medicines Agency’s EudraVigilance electronic system 
according to EU Regulation 536/2014, and to all country regulatory authorities where the study 
is being conducted, according to local applicable regulations.  
8.5.5. 
Serious Adverse Event Reporting  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will evaluate the reported SAEs, including confirmation of relatedness and assessment 
of expectedness. The Sponsor has processes for safety reports for identification, recording, and 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 101 of 181 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs) according to 
local regulatory requirements. The Sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators 
(see Section 10.1.3). 
In the event of an accidental or intentional overdose by a patient, the site staff must immediately 
inform Clinical Safety. The eCRF must be updated to reflect this information. In the event that 
the overdose is associated with an AE and/or SAE, the 2 events should be linked. In the event an 
AE and or SAE is associated with an overdose, the appropriate report form must be completed 
detailing the AE and the overdose details.  
All SAEs, regardless of causality, that occur from time of informed consent to SFU (28 days 
[+ 7 days] after the last dose), are to be recorded on the appropriate eCRF  and must be reported 
to Clinical Safety within 24 hours of the knowledge of the occurrence (this refers to any AE that 
meets any of the aforementioned serious criteria). All SAEs that the Investigator considers 
related to study drug occurring after the 28-day follow-up period must be reported to the 
Sponsor.  
SAE Reporting via Paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the SAE coordinator. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contact information for SAE reporting can be found in the SAE form. 
The Investigator will be requested to supply detailed information regarding the event. SAEs must 
also be reported to the IRB/ IEC and a copy of that report must be retained at the investigative 
site and filed in the Investigator Site File in accordance with the requirements of that institution.  
Although not considered an AE per se, the Sponsor must be notified of any patient or patient’s 
partner who becomes pregnant during a clinical study (refer to Section 8.5.7).  
8.5.6. 
Serious Adverse Event Follow-up 
For all SAEs occurring during the study, the Investigator must submit follow-up reports to the 
Sponsor regarding the status of the SAE and the patient’s subsequent course until the SAE has 
resolved, or until the condition stabilizes or is deemed chronic (in the case of persistent 
impairment), or the patient dies. 
8.5.7. 
Pregnancy Reporting 
If the patient or partner of a patient participating in the study becomes pregnant during the study 
or within 6 months of discontinuing study drug or 12 months after discontinuing rituximab, 
whichever is later, the Investigator should report the pregnancy to Clinical Safety within 
24 hours of being notified. Clinical Safety will then forward the Pregnancy form to the 
Investigator for completion. 
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 102 of 181 
The patient or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Clinical Safety. At the completion of the pregnancy, the Investigator will document the outcome 
of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification 
as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.5.8. 
Second Primary Malignancy Reporting 
The Investigator must follow up with all patients for up to 5 years from the start of study 
treatment to monitor for the occurrence of any SPM events. SPM events should be reported to 
the Sponsor, regardless of seriousness or causal attribution to study medication. For patients who 
cross over to pirtobrutinib, patients are to be followed for 5 years starting from when they started 
taking pirtobrutinib.  
8.6. 
Treatment of Overdose 
For Arm A, refer to the Pirtobrutinib IB for further information, recommendations and guidance. 
For Arm B, refer to the local product label for idelalisib, rituximab, or bendamustine for 
available information on the signs, symptoms, and treatment of overdose. 
8.7. 
Pharmacokinetics 
At the visits and times specified in the SoA (Section 1.3), blood samples of approximately 2 mL 
each will be collected to determine the plasma concentrations of pirtobrutinib in Arm A only. 
A maximum of 6 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the Investigator and the Sponsor. Instructions for the 
collection and handling of blood samples will be provided by the Sponsor. The actual date and 
time (24-hour clock time) of each sampling and prior dose will be recorded. 
 be collected 
 and 
 
 Samples are to be drawn 
 and exact 
time of sample collection should be recorded. In addition, time of previous dose should be 
recorded. 
 may also be assessed in patients when considered necessary by the 
Investigator to understand exposure in relationship to possible safety.  
 
 will be retained for 
 following last 
patient visit for the study. During this time, 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 103 of 181 
8.9. 
Genetics 
8.9.1. 
Bone Marrow 
 Biopsy 
 
, in accordance with the SoAs (Section 1.3). Biopsy is required at 
Screening 
. For central assessment 
of CR, bone marrow biopsy 
 samples should also be collected in accordance with the 
SoAs (Section 1.3) 
. Optional 
bone marrow biopsy 
 sample  for confirmation of PD may be collected to establish 
the criteria of PD per iwCLL 2018 if indicated. Guidance on sample collection and timing is 
provided in the SoAs (Section 1.3) and the Laboratory Manual. 
8.9.2. 
Pathology and Molecular Reports 
Anonymized/redacted pathology report(s) confirming histologic diagnosis and relevant 
prognostic biomarkers (e.g., IGHV, TP53 mutations, karyotype status, fluorescence in-situ 
hybridization [FISH] for del 17p, del 11q), should be submitted. 
 
 
  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 104 of 181 
 
  
8.11. 
Immunogenicity Assessments 
Not applicable for this Phase 3 protocol. 
8.12. 
Medical Resource Utilization and Health Economics 
8.12.1. 
Patient-Reported Outcomes  
Patient-reported outcome questionnaires will be administered electronically according to the SoA 
for patient-reported outcomes (PRO; Section 1.3) in countries where the questionnaires have 
been translated into the native language of the region and linguistically validated. Only patients 
who are literate in an available translation will complete the questionnaires. The PROs will be 
used to evaluate changes in CLL/SLL symptoms, physical function, and other health-related 
quality of life (HRQoL) outcomes of Arm A compared to Arm B, and generate health utility 
data. Questionnaires will be administered electronically using a provisioned ePRO device or 
through web-based method. Patients will complete the specified baseline assessments 
electronically at clinic at C1D1 prior to their first dose of study drug. Subsequent ePRO 
assessments will be self-completed electronically according to the SoA for PROs (Section 1.3). 
At EOT and SFU, the site will trigger the specified EOT and SFU assessments on the patient’s 
ePRO device; therefore patients will be asked to bring their device with them for all clinic visits. 
If possible, baseline (C1D1), EOT, and SFU questionnaire completion should occur prior to 
extensive interaction with site health practitioners regarding the patient’s status, or receipt of 
laboratory results and/or additional treatments.  
While individual patients may vary in their response time, data from prior research among 
patients with advanced cancers suggest that 20 items can be completed in an average of less than 
4 minutes using an electronic device.  
8.12.1.1. EORTC QLQ-C30 
Health-related quality of life will be assessed using the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0 (EORTC QLQ-C30; 
Aaronson et al. 1993). At some patient visits the full scale will be administered and at other 
times, only selected items. 
The full EORTC QLQ-C30 self-reported general cancer instrument consists of 30 items covering 
3 dimensions regarding the patient’s experience in the past 7 days: 
• Global health status/quality of life (2 items) 
• Functional scales (15 total items addressing either physical, role, emotional, cognitive, or 
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 105 of 181 
social functioning) 
• Symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, or financial impact) 
8.12.1.3. EORTC IL19: Physical Function 
The EORTC IL19 consists of 5 items that are identical to the physical functioning score 
(items 1-5) of the EORTC QLQ-C30. This assessment will be completed by patients at 
time-points in between administration of the full EORTC QLQ-C30 in order to minimize patient 
burden. 
8.12.1.5. EQ-5D-5L 
Health status will be assessed using the 5-level-EuroQol (EQ-5D-5L; Janssen et al. 2013). 
These utility measures are an important input for economic evaluations by global health 
technology assessment organizations that examine the value of treatment interventions. 
Patients will complete the 5-dimension (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression), 5-level (no problem, slight, moderate, severe, or extreme problem) 
assessment according to the SoA. Additionally, patients will indicate their current health status 
by marking on a visual analog scale ranging from 100 (best imaginable health state) to 0 
(worst imaginable health state) as of “today.” The EQ-5D-5L is designed for self-completion 
by respondents, is cognitively simple, takes only a few minutes to complete, and will be 
administered electronically at the study site according to the SoA prior to receiving study 
treatment.  
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 106 of 181 
 
 
8.12.2. 
Medical Resource Utilization 
Medical resource utilization will be collected in the eCRF by the Investigator and study site 
personnel for all patients throughout the study. Protocol-mandated procedures, tests, and 
encounters are excluded. 
The data collected will include: 
• Hospitalization (yes or no) and duration of hospitalization (admission and discharge dates) 
• Emergency room visits (yes and number of events, or no) 
• Supportive care medications (GCSF use, analgesics, transfusions) 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 107 of 181 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
Treatment with pirtobrutinib will provide a clinically meaningful increase in PFS over treatment 
with Investigator’s choice of either idelalisib plus rituximab (IdelaR) or bendamustine plus 
rituximab (BR) (Arm B) in BTK inhibitor pretreated CLL/SLL patients. 
9.2. 
Sample Size Determination 
The study is expected to enroll approximately 250 patients. Patients will be randomized in a 
1:1 ratio between pirtobrutinib (Arm A) and comparator (Arm B). The study is sized to achieve 
approximately 
 power to detect a targeted hazard ratio (HR) of 
 in PFS which, under the 
model assumptions, translates into a 
 relative improvement in median PFS comparing 
pirtobrutinib arm to the comparator arm, at the 
. 
This sample size calculation was based on a median PFS time of 
 in the comparator 
arm versus a median PFS time of 
 in pirtobrutinib arm. The accrual period is assumed 
to be approximately 
, and 
 by the time of the final 
PFS analysis. 
9.3. 
Populations for Analyses 
For purposes of analysis, the populations are defined as follows: 
Table 9.1 
Analysis Populations 
Population 
Description 
Intention to treat (ITT) 
All randomized patients, even if a patient does not take the assigned treatment, does 
not receive the correct treatment, or otherwise does not follow the protocol. Patients 
will be analyzed according to the treatment group they were assigned to regardless 
of what actual treatment they receive. 
Safety 
All randomized patients who take at least 1 dose (including a partial dose) of study 
treatment. Analysis of safety data will be based on the actual treatment a patient 
received on the first study treatment administration regardless of which treatment 
they were randomized to receive (“as treated”). 
Data collected for Arm B patients who cross over to pirtobrutinib monotherapy may be analyzed 
and reported as a stand-alone group, independent of Arm A or Arm B. 
9.4. 
Statistical Analyses 
One final analysis is planned. The analysis is planned when approximately 
 
 have been observed, which is expected to occur approximately 
 -after the first 
patient has been randomized, under the assumption of treatment effect and enrollment projection 
(Section 9.2).  
9.4.1. 
General Statistical Considerations 
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 108 of 181 
All tests of treatment effects will be conducted at a 
, unless otherwise 
stated. 
Continuous variables will be summarized using descriptive statistics (i.e., number of patients, 
mean, median, standard deviation, minimum, and maximum). Categorical variables will be 
summarized by frequency and its corresponding percentage. 
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the Statistical Analysis Plan (SAP), where appropriate. 
Adjustments to the planned analyses are described in the CSR. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. More details for the analyses will be 
provided in the SAP. The SAP will be finalized before database lock. Any changes to the 
methods described in the final SAP will be described and justified in the clinical study report. 
9.4.2. 
Study Endpoints 
The primary, secondary, 
 endpoints are displayed with the objectives for the 
study in Section 3. 
9.4.3. 
Treatment Group Comparability 
9.4.3.1. 
Patient Disposition 
A detailed description of patient disposition will be provided. 
9.4.3.2. 
Patient Characteristics 
Patient demographic and baseline characteristics will be summarized using the ITT population. 
Baseline disease characteristics, prior anticancer therapies, historical illness, and pre-existing 
conditions will also be summarized. 
9.4.3.3. 
Concomitant Medication 
A summary of preferred names of concomitant medication by treatment arm by decreasing 
frequency will be generated.  
9.4.3.4. 
Prior and Subsequent Anticancer Therapy 
Prior and subsequent anticancer therapy used to treat CLL will be summarized based on line of 
therapy and type of therapy. 
9.4.3.5. 
Extent of Exposure 
The duration on therapy, dose omissions, dose reductions, dose delays, and dose intensity for 
each drug will be summarized for all treated patients by arms as appropriate. 
9.4.4. 
Efficacy Analyses 
All efficacy analyses will be performed using the ITT population, unless otherwise specified. 
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 109 of 181 
9.4.4.1. 
Analysis of Primary Endpoint 
The primary efficacy endpoint of PFS is defined as the time from the date of randomization until 
PD (assessed by the IRC per iwCLL 2018 criteria, Section 10.6, Appendix 6) or death from any 
cause, whichever occurs first. Patients not meeting these criteria and alive by the analysis data 
cutoff date will be censored and the detailed censoring rules will be specified in the SAP. 
, will be used for the primary comparison of 
PFS. The HR and its 95% confidence interval (CI) will be computed from 
 
. In addition, median PFS and its 95% CI, as well as PFS rates and associated 
95% CI at selected timepoints, will be provided using the 
. Sensitivity 
analyses for PFS will be described in the SAP. 
The final analysis is planned when approximately 
 have been 
observed, which are expected to occur approximately 
 after the first patient has been 
randomized under the assumption of treatment effect and enrollment projection (Section 9.2). 
Superiority for final analyses are anticipated to be assessed 
 
 
9.4.4.2. 
Analyses of Secondary Endpoints 
The SAP will describe the key secondary endpoints to be tested and the statistical methods to be 
used to ensure 
 
PFS per Investigator assessment is defined as the time from the date of randomization until PD 
(per iwCLL 2018 criteria, Section 10.6, Appendix 6) or death from any cause, whichever occurs 
first. Similar censoring rules and analysis methods will be applied as described for PFS per IRC. 
ORR is defined as the proportion of patients who achieve a best overall response (BOR) of CR, 
CRi, nPR, or partial remission (PR) at or before the initiation of subsequent anticancer therapy. 
The ORR, with 
, will be summarized for each treatment arm. ORR will be compared 
between Arm A and Arm B using 
 
. The ORR will be evaluated according to both IRC and Investigator 
assessment per iwCLL 2018 criteria. ORR including PR with lymphocytosis (PRL) will be 
assessed by the Investigator and IRC will also be analyzed with the same analysis method used 
for ORR.  
DOR is defined as the time from the date of the first documented response of CR, CRi, nPR, or 
PR to the earlier of the documentation of definitive PD (per iwCLL 2018 criteria, Section 10.6) 
or death from any cause. Following first documentation of CR, CRi, nPR, or PR patients who are 
alive and without documented PD as of a data analysis cutoff date will be censored. Similar 
censoring rules will be applied as described for PFS. DOR according to both IRC and 
Investigator assessment will be evaluated. Median DOR 
, as well as DOR rates 
and associated 
 
OS is defined as the time from randomization until death from any cause. If the patient is alive or 
lost to follow-up at the time of data analysis, OS data will be censored on the last date the patient 
is known to be alive. 
TTNT is defined as time from the date of randomization to the date of the initiation of the next 
systemic anticancer therapy for CLL/SLL or the first dose date of pirtobrutinib for Arm B 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 110 of 181 
patients who crossed over to receive pirtobrutinib or death due to any cause, whichever occurred 
first. 
EFS is defined as the time from date of randomization to the date of PD or start of new treatment 
for CLL/SLL or discontinuation from treatment due to toxicity or death, whichever occurs first. 
The analysis methods for OS, TTNT, and EFS will be similar to those described for PFS. Details 
of the censoring rules for these endpoints will be provided in SAP.  
9.4.5. 
Safety Analyses 
Safety data will be summarized for the safety population. The baseline value for the safety 
analysis is defined as the value collected at the time closest to and before the start of study drug 
administration. 
9.4.5.1. 
Adverse Events 
AEs will be graded by the Investigator according to the NCI CTCAE v5.0 or higher for 
nonhematologic and hematologic AEs. Each AE verbatim term will be coded to a system organ 
class and a preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). 
All TEAEs will be summarized by treatment arm. AE incidence rates will also be summarized by 
severity and relationship to study drug.  
Grade 3 or Grade 4 TEAEs; TEAEs leading to permanent study drug treatment discontinuation; 
TEAEs leading to dose modification; serious TEAEs; and TEAEs resulting in death will be 
summarized by treatment arm. 
9.4.5.2. 
Clinical Laboratory Tests 
For gradable clinical laboratory parameters, a summary of worst postbaseline toxicity grade will 
be provided in the treatment-emergent period by treatment arm and worst toxicity grade. The 
difference in percentages will be displayed.  
Additional safety endpoints including ECOG, vital signs, and weight will be summarized 
descriptively with further details provided in the SAP. 
9.4.6. 
Pharmacokinetic/Pharmacodynamic Analyses 
Pirtobrutinib plasma concentrations will be summarized by descriptive statistics. 
 
 
 
 
9.4.7. 
Other Analyses 
9.4.7.1. 
Patient-Reported Outcomes and Medical Resource Utilization 
For each PRO instrument, percentage compliance will be calculated as the number of completed 
assessments divided by the number of expected assessments at each time point. Data will be 
separately summarized using descriptive statistics. 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 111 of 181 
Time to worsening in CLL/SLL-related symptoms and physical functioning will be described 
. A comparative analysis between the 2 arms will be conducted 
using 
. Further details of the PRO secondary 
endpoints will be provided in the PRO SAP. 
Details for the analyses 
 
 will also be provided in the PRO SAP.  
Frequency counts of hospitalizations, emergency room visits, GCSF use, and transfusions will be 
reported descriptively for each treatment arm. 
9.4.7.2. 
Subgroup Analyses 
Details of subgroup analysis will be provided in SAP. 
9.5. 
Interim Analyses  
No interim analysis is planned. 
9.6. 
Data Monitoring Committee 
The DMC will review the safety data periodically and provide recommendations according to the 
DMC charter. 
The first safety data review will be performed by the DMC after approximately 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 112 of 181 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences International 
Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) GCP Guidelines. 
• Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any substantial amendments or addenda and amended ICFs to the protocol will require 
IRB/IEC approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study patients. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
o Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
o Reporting to the Sponsor or designee significant issues related to patient safety, patient 
rights, or data integrity. 
10.1.2. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the patient or his/her legally authorized representative and answer all 
questions regarding the study. 
• Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 113 of 181 
Portability and Accountability Act requirements, where applicable, and the IRB/IEC or study 
center. 
• The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study, before initiation of any study-related Screening 
procedure and the date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF. 
• Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• Patients must be consented for crossover treatment. 
• A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative and is kept on file. 
• Patients who are rescreened are required to sign a new ICF. 
10.1.3. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee  
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC 
according to their institutional policy by the Investigator or Sponsor (or Sponsor designee) 
according to country requirements. Copies of each report and documentation of IRB/IEC 
notification and acknowledgement of receipt will be kept in the Investigator’s study file.  
10.1.4. 
Sponsor Safety Reporting to Regulatory Authorities 
SAE Regulatory Reporting 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Pirtobrutinib IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
10.1.5. 
Data Protection  
• Patients will be assigned a unique identifier by the Sponsor to protect the patient’s personal 
data. Any patient information, such as records, datasets, or tissue samples that are transferred 
to the Sponsor will contain the identifier only. Patient names or any information which would 
make the patient identifiable will not be transferred. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 114 of 181 
• The patient must be informed that the patient’s personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the patient who will be required to give consent for their data to be used as 
described in the informed consent. This is done by the site personnel through the informed 
consent process. 
• The patient must be informed through the informed consent by the site personnel that their 
medical records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. 
• The Sponsor has processes in place to ensure data protection, information security and data 
integrity. These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach. 
10.1.6. 
Independent Review Committee Structure 
The primary endpoint, PFS, will be assessed by IRC. A blinded independent review committee 
will consist of independent radiologists to perform response assessments and determination of 
PD per iwCLL 2018 criteria (Section 10.6, Appendix 6). 
10.1.7. 
Dissemination of Clinical Study Data 
Dissemination of study data will be performed according to all applicable Sponsor and 
international policies. The Sponsor will disclose a summary of study information, including 
tabular study results on publicly available websites, where required by local law or regulations 
within the specified timeframes. 
10.1.8. 
Data Quality Assurance 
• All patient data relating to the study will be recorded in the eCRF unless transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for the time period outlined in the Clinical Trial Agreement 
(CTA) unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 115 of 181 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
• Provide instructional material to the study sites, as appropriate 
• Provide Sponsor start-up training to instruct the Investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, and study 
procedures. 
• Make periodic visits to the study site 
• Be available for consultation and stay in contact with the study site personnel by e-mail, 
telephone, and/or fax 
• Review and verify data reported to detect potential errors  
In addition, the Sponsor or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by the Sponsor or 
its representatives and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs. 
The Investigator will keep records of all original source data. This might include laboratory tests, 
medical records, and clinical notes. If requested, the Investigator will provide the Sponsor, 
applicable regulatory agencies, and applicable IRBs/IECs with direct access to original source 
documents. 
10.1.9. 
Data Capture System 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the Sponsor.  
An EDC system will be used in this study for the collection of eCRF data. The Investigator 
maintains a separate source for the data entered by the Investigator or designee into the Sponsor-
provided EDC system. The Investigator is responsible for the identification of any data to be 
considered source and for the confirmation that data reported are accurate and complete by 
signing the eCRF. 
Additionally, ePRO data questionnaires and scales will be directly recorded by the patient, into 
an instrument (e.g., an electronic device). The ePRO data will serve as the source documentation 
and the Investigator does not maintain a separate, written or electronic record of these data. 
Data collected via the Sponsor-provided data capture system will be stored at a third party. The 
Investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 116 of 181 
10.1.10. 
Source Documents 
• Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
10.1.11. 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study treatment development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the patient and 
assures appropriate patient therapy and/or follow-up. 
10.1.11.1. Discontinuation of the Study 
The study will be discontinued if the Sponsor judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and GCP. 
10.1.11.2. Discontinuation of Study Sites 
Study site participation may be discontinued if the Sponsor, the Investigator, or the IRB/IEC of 
the study site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP. 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 117 of 181 
10.2. 
Appendix 2: Contraceptive Guidance and Pregnancy Information 
Willingness of men and WOCBP, and their partners, to observe barrier and highly effective birth 
control methods as outlined below for the duration of treatment and for 6 months following the 
last dose of study treatment or 12 months after the last dose of rituximab, whichever is later. 
WOCBP are defined as those following menarche, and who are not postmenopausal (or 2 years 
of non-therapy-induced amenorrhea, or surgically sterile). WOCBP must utilize highly effective 
contraception methods as outlined below. In addition, male partners must use a barrier method 
(condoms) for the duration of treatment and for 6 months following the last dose of study 
treatment or 12 months after the last dose of rituximab, whichever is later. Male patients with 
partners who are WOCBP must use a barrier method (condoms) and their partner must also use a 
highly effective form of contraception as listed below for the duration of treatment and for 
6 months following the last dose of study treatment or 12 months after the last dose of rituximab, 
whichever is later.  
Highly effective birth control methods with a failure rate of less than 1% per year when 
used consistently and correctly are recommended (CTFG 2020): 
a. Combined estrogen and progestin containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally, or transdermally 
b. Progestin-only hormonal contraception associated with inhibition of ovulation given orally, 
by injection, or by implant 
c. Intrauterine device (IUD) 
d. Intrauterine hormone-releasing system (IUS) 
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence: Considered a highly effective method only if defined as refraining from 
heterosexual intercourse during an entire period of risk associated with the study treatment. 
The reliability of sexual abstinence will be evaluated in relation to the duration of the study 
and to the usual lifestyle of the patient. 
Notes:  
• Women with a history of breast cancer may not use hormone-containing contraception 
(a, b, or d). One of the other listed methods above should be selected. 
• Women of childbearing potential using hormonal contraception methods should also use 
a barrier method as a second form of contraception. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 118 of 181 
Birth control methods that are considered unacceptable or insufficient alone for this clinical 
trial include (CTFG 2020): 
a. progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
b. male or female condom with or without spermicide 
c. cap, diaphragm or sponge with spermicide 
d. combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) 
e. periodic abstinence (calendar, symptothermal, or post-ovulation methods) 
f. withdrawal (coitus interruptus) 
g. spermicide only 
h. lactational amenorrhea method 
Notes:  
• 
Condom/diaphragm with spermicide is not adequate alone. 
• 
Women with a history of breast cancer may not use hormone-containing contraception 
(a). One of the other listed methods above should be selected. 
• 
Sperm donation and oocyte donation are prohibited during the duration of participation 
on this protocol and for 6 months after the last dose of study drug, or at least 12 months 
following last dose of rituximab, whichever is later. 
 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 119 of 181 
10.3. 
Appendix 3: Liver Safety 
The hepatic monitoring tests will be conducted in accordance with the SoAs (Section 1.3). 
Selected tests may be obtained in the event of a clinically significant treatment-emergent hepatic 
abnormality while on study and should be obtained in accordance with local guidelines and/or as 
directed by a local hepatologist when appropriate. Studies may be required in follow-up and will 
be decided upon between the Investigator and the Sponsor when appropriate. 
Hepatic Monitoring Tests 
Hepatic Hematology  
Haptoglobin  
HGB 
HCT 
Hepatic Coagulation 
Erythrocytes (RBC) 
Prothrombin time 
Leukocytes (WBC) 
INR 
Neutrophils  
Lymphocytes 
Hepatic Serologies  
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
Hepatitis B Core antibody 
Hepatic Chemistry  
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
ALP 
 
ALT 
Other Serology Testing  
AST 
CMV/EBV testing (antibody and/or DNA) 
GGT 
HBV DNA testing 
CPK 
 
Recommended Autoimmune Serology 
 
Antinuclear antibody a 
 
Antismooth muscle antibody b 
a Assayed by local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 120 of 181 
10.4. 
Appendix 4: Restricted and Prohibited Concomitant Medication 
The following tables describe the drug class and associated medications that will be restricted or 
be used with caution during the study treatment period. Patients who, in the assessment by the 
Investigator, require the use of any of the prohibited treatments for clinical management should 
be removed from the study. Refer to Section 6.5 for additional information. 
Note: The lists below are not exhaustive. Also refer to: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm. 
Note: Non-systemic (e.g., topical creams, eye drops, mouthwashes, etc.) applications are 
permissible. 
Table 10.1 
Inhibitors of CYP3A4 
Inhibitors of CYP3A4 
Strong inhibitors a 
Moderate inhibitors b 
boceprevir 
amprenavir 
clarithromycin 
aprepitant 
conivaptan 
atazanavir 
grapefruit juice /products 
ciprofloxacin 
indinavir 
darunavir 
itraconazole 
diltiazem 
ketoconazole 
erythromycin 
lopinavir 
fluconazole 
mibefradil 
fosamprenavir 
nefazodone 
imatinib 
nelfinavir 
verapamil 
posaconazole 
 
ritonavir 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
Star fruit /products 
 
Seville oranges /products 
 
a Increases the AUC of sensitive index substrates of a given metabolic pathway by ≥ 5-fold. 
b Increases the AUC of sensitive index substrates of a given metabolic pathway by 2- to 5-fold. 
Note: The list above is not exhaustive. Also refer to: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm0936
64.htm 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 121 of 181 
Table 10.2 
Inducers of CYP3A4 
Inducers of CYP3A4 
Strong Inducers 
Moderate Inducers 
apalutamide 
bosentan 
carbamazepine 
efavirenz 
enzalutamide 
etravirine 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
 
St. John’s wort 
 
Note: Strong and moderate inducers decrease the AUC of sensitive index substrates of a given metabolic pathway 
by ≥ 80%, and ≥ 50% to < 80% respectively. 
Note: The list above is not exhaustive. Also refer to: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm09366
4.htm 
 
Table 10.3 
CYP3A Sensitive Substrates 
CYP3A Sensitive Substrates 
abemaciclib 
darunavir 
lopinavir 
simvastatin 
acalabrutinib 
dasatinib 
lovastatin 
sirolimus 
alectinib 
dronedarone 
lumefantrine 
tacrolimus 
alfentanil 
ebastine  
lurasidone 
ticagrelor 
aprepitant (also 
fosaprepitant) 
eliglustat 
maraviroc 
tipranavir 
atazanavir 
elvitegravir 
midazolam 
tolvaptan 
atorvastatin 
entrectinib 
midostaurin 
triazolam 
avanafil 
eplerenone 
naloxegol 
ulipristal 
avapritinib 
everolimus 
neratinib 
uprogepant 
bosutinib 
felodipine 
nisoldipine 
vardenafil 
brotizolam 
ibrutinib 
paritaprevir 
venetoclax 
budesonide 
indinavir 
quetiapine 
vinblastine 
buspirone 
isavuconazole (prodrug is 
isavuconazonium sulfate) 
quinidine 
zanubrutinib 
cobimetinib 
ivabradine 
saquinavir 
 
conivaptan 
ivacaftor (also ivacaftor 
with lumacaftor, ivacaftor 
with tezacaftor) 
sildenafil 
 
darifenacin 
lomitapide 
simeprevir 
 
Note: Drugs not marketed in the US or Europe have been omitted. 
Source: University of Washington Drug Interaction Solutions List of CYP3A Sensitive Substrates accessed 14 May 2020. 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 122 of 181 
Table 10.4 
P-gp Substrates 
Examples of P-gp Substrates 
dabigatran 
loperamide 
digoxin 
verapamil 
fexofenadine 
 
Note: The above list is not exhaustive. Also refer to: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
 
Table 10.5 
CYP2C8 Substrates 
Examples of CYP Substrates 
montelukast 
rosiglitazone 
pioglitazone 
repaglinide 
Note: the above list is not exhaustive. Also refer to: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
 
Table 10.6  
BCRP Substrates 
Examples of BCRP Substrates 
rosuvastatin 
sulfasalazine 
Note: the above list is not exhaustive. Also refer to: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 123 of 181 
10.5. 
Appendix 5: Creatinine Clearance Formula 
Creatinine clearance (CrCl) will be assessed using the following formula: 
Note: This formula has to be used for calculating CrCl from local laboratory results only. 
For serum creatinine concentration in mg/dL: 
CrCl  =  
 
(140 – agea) × (body weighta) × 0.85 (if female) 
(mL/min)  
 
 
serum creatinine (mg/dL) × 72 
 
a Age in years, weight in kilograms. 
Source: Cockcroft and Gault 1976. 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 124 of 181 
10.6. 
Appendix 6: iwCLL 2018 Response Criteria 
Group 
Parameter 
CR 
PR 
PD 
SD 
A 
Lymph nodesa 
None ≥ 1.5 cm 
Decrease ≥ 50% 
(from baseline)a 
Increase ≥ 50% 
from nadir 
Change of -49% to 
+49% 
Liver and/or 
spleen sizeb 
Spleen size < 13 
cm; liver size 
normal 
Decrease ≥ 50% 
(from baseline) 
Increase ≥ 50% 
from nadir 
Change of -49% to 
+49% 
Constitutional 
symptoms 
None 
Any 
Any 
Any 
Circulating 
lymphocyte count 
Normal 
Decrease ≥ 50% 
from baseline 
Increase ≥ 50% 
over nadir 
Change of -49% to 
+49% 
B 
Platelet count 
≥ 100 × 109/L 
≥ 100 × 109/L or 
increase ≥ 50% 
over baseline 
Decrease of ≥ 50% 
from baseline 
secondary to CLL 
Change of -49% to 
+49% 
Hemoglobin 
≥ 11.0 g/dL (un-
transfused and 
without 
erythropoietin) 
≥ 11.0 g/dL or 
increase ≥ 50% 
over baseline 
Decrease of 
≥ 2 g/dL from 
baseline secondary 
to CLL 
Increase 
< 11.0 g/dL or 
< 50% over 
baseline, or 
decrease < 2 g/dL 
Marrow 
Normo-cellular, 
no CLL cells, no 
B-lymphoid 
nodules 
Presence of CLL 
cells, or of B-
lymphoid nodules, 
or not done 
Increase of CLL 
cells by ≥ 50% on 
successive biopsies 
No change in 
marrow infiltrate 
Source: (Hallek et al. 2018). 
Abbreviations: CLL = chronic lymphocytic leukemia; CR = complete remission (all of the criteria have to be met); 
PD = progressive disease (at least 1 of the criteria of group A or group B has to be met); PR = partial remission (for 
a PR, at least 2 of the parameters of group A and 1 parameter of group B need to improve if previously abnormal; 
if only 1 parameter of both groups A and B is abnormal before therapy, only 1 needs to improve); SD = stable 
disease (all of the criteria have to be met; constitutional symptoms alone do not define PD). 
a Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination in clinical 
studies or by physical examination 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 studies and 
be recorded according to the definition used in a study protocol. 
In addition to the CR, PR, PD and SD response definition as listed in the table above, the 
protocol requires response assessments of CRi, nPR, and PR-L, as explained below: 
• BTK inhibitors are known to cause lymphocytosis due to redistribution of lymphocytes. In 
BTK inhibitors or compounds with similar mechanism of action, initial absolute lymphocyte 
count (ALC) progression with associated PR in other categories during therapy is usually 
indicative of PR-L (Cheson and Byrd et al. 2012).  
• For CRi response, patients must fulfill all criteria for a CR with persistent anemia, 
neutropenia or thrombocytopenia and the Investigator must attribute these cytopenias as 
related to investigational drug and not due to the underlying disease.  
• For nPR, patients must fulfill all criteria for a CR, but the bone marrow biopsy/
 
shows B-lymphoid nodules which are evidence for residual disease.  
Isolated new lymphocytosis initially occurring during Cycle 1 will not be used as criteria for 
determining PD. 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 125 of 181 
10.7. Appendix 7: QTcF Measurement Adjustment in Patients with a 
Widened QRS Complex > 110 ms 
Fridericia’s formula: QTcF (s) = QT (s)/(RR (s) 0.33) 
The duration of the ECG QT interval reflects the combination of cardiac depolarization which is 
reflected by the QRS interval and cardiac repolarization, which is defined by the JT interval. 
 
 
Normal values for the rate-corrected QTc interval are defined largely from populations of 
patients with normal QRS durations, without bundle branch blocks or intraventricular conduction 
delays. The Fridericia heart rate-corrected QTc interval is the most commonly used methodology 
in drug development, since it usually is the most accurate. In the setting of a widened QRS 
complex (> 110 ms), however, using the QTcF interval measurement may lead to overestimating 
cardiac repolarization, since the QTcF would be prolonged due to the contribution from the 
widened QRS complex; in other words, the QTcF interval could be prolonged despite cardiac 
repolarization being normal (i.e., a normal JTc interval). For example, if the QRS duration was 
150 ms and the QTcF was 500 ms, cardiac repolarization is not meaningfully prolonged when it 
is considered that a normal QRS duration is conservatively 90 ms. So, in this case, 60 ms 
(150 ms–90 ms) of the QTcF of 500 ms is due to excessive QRS prolongation and thus the QTcF 
“adjusted” for the QRS widening is 440 ms (500 ms– [150 ms– 90 ms]). 
Thus, for this protocol, in patients with a QRS duration > 110 ms, a QTcF adjusted for the 
widened QRS duration will be used to assess if a patient meets criteria for protocol exclusion, 
drug hold, or discontinuation using the below formula: 
 “Adjusted QTcF” = measured QTcF - [measured QRS- 90 ms]. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 126 of 181 
10.8. 
Appendix 8: Abbreviations and Definitions 
Term 
Definition 
ADL 
activities of daily living  
AE 
adverse event: Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship 
with this treatment. An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
AIHA 
autoimmune hemolytic anemia  
ALC 
absolute lymphocyte count  
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the concentration versus time curve 
BBB 
bundle branch block 
BCL2 
B-cell lymphoma 2 
BCR 
B-cell receptor 
BCRP 
breast cancer resistance protein 
BID 
twice a day 
BMX 
bone marrow tyrosine kinase gene on chromosome X 
BOR 
best overall response 
BR 
bendamustine with rituximab 
BSA 
body surface area 
BTK 
Bruton’s tyrosine kinase 
C1D1 
Cycle 1 Day 1 
C1D2 
Cycle 1 Day 2 
C1D8 
Cycle 1 Day 8 
C1D15 
Cycle 1 Day 15 
C2D1 
Cycle 2 Day 1 
C2D15 
Cycle 2 Day 15 
C3D1 
Cycle 3 Day 1 
C4D1 
Cycle 4 Day 1 
C5D1 
Cycle 5 Day 1 
C6D1 
Cycle 6 Day 1 
C7D1 
Cycle 7 Day 1 
C481 
cysteine residue at position 481 
CAP 
College of American Pathologists 
CAR-T 
chimeric antigen receptor-modified T-cells  
cfDNA 
cell free DNA 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CLL/SLL 
chronic lymphocytic leukemia/small lymphocytic lymphoma 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 127 of 181 
Term 
Definition 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CO 
crossover 
COPD 
chronic obstructive pulmonary disease 
CPK 
creatine phosphokinase 
CR 
complete remission 
CRF 
case report form 
CRi 
complete remission with incomplete marrow recovery 
CrCl 
creatinine clearance 
CSR 
clinical study report 
CT 
computed tomography 
CTA 
Clinical Trial Agreement 
CTCAE 
Common Terminology Criteria in Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CYP 
cytochrome P450 
CYP3A4 
cytochrome P450 3A4  
DAG 
diacyl glycerol  
DCR 
disease control rate 
DLBCL 
diffuse large B-cell lymphoma  
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DRESS 
drug reaction with eosinophilia and systemic symptoms 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EFS  
event free survival 
enroll 
The act of assigning a patient to a treatment. Patients who are enrolled in the study are those 
who have been assigned to a treatment. 
enter 
patients entered into a study are those who sign the informed consent form directly or through 
their legally acceptable representatives. 
EORTC 
European Organisation for Research and Treatment of Cancer Quality of Life questionnaire 
EORTC IL19 
European Organisation for Research and Treatment of Cancer Item Library 19 
 
 
 
 
EORTC QLQ-
C30 PF 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
Core 30 Version 3.0 
EOT 
End of Treatment 
ePRO 
electronic patient-reported outcome  
EQ-5D-5L 
5-level-EuroQol 
ERK 
extracellular signal-regulated kinase  
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 128 of 181 
Term 
Definition 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FOIA 
Freedom of Information Act 
FDG 
fluorodeoxyglucose 
GCP 
Good Clinical Practice 
GCSF 
granulocyte-colony-stimulating factor 
GI 
gastrointestinal 
GnRH 
gonadotropin-releasing hormone 
GVHD 
graft versus host disease 
HBc 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen  
HBV 
Hepatitis B virus  
HCV 
Hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life  
IB 
Investigator’s Brochure 
IC90 
90% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IdelaR 
idelalisib with rituximab  
IEC 
International Electrotechnical Committee  
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IGHV 
immunoglobulin heavy chain variable region gene 
IgM 
immunoglobulin M 
informed 
consent 
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to the 
patient’s decision to participate. Informed consent is documented by means of a written, 
signed, and dated informed consent form. 
INR 
international normalized ratio  
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form. 
IP3 
inositol 3-phosphate  
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ISO/IEC 
International Organization for Standardization/International Electrotechnical Committee 
ITK 
inducible T-cell kinase 
ITP 
idiopathic thrombocytopenic purpura  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 129 of 181 
Term 
Definition 
ITT 
intention to treat: The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (i.e., the planned 
treatment regimen) rather than the actual treatment given. It has the consequence that patient 
allocated to a treatment group should be followed up, assessed, and analyzed as members of 
that group irrespective of their compliance to the planned course of treatment. 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IXRS 
interactive voice/web response system 
LDH 
lactate dehydrogenase 
LHRH 
luteinizing hormone-releasing hormone 
LTFU 
Long-Term Follow-up 
LVEF 
left ventricular ejection fraction 
LYN 
a protein kinase that in humans is encoded by the LYN gene 
MAPK 
mitogen-activated protein kinase  
MCL 
mantle cell lymphoma 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximal tolerated dose 
MZL 
marginal zone lymphoma 
NCCN 
National Comprehensive Cancer Network 
NCI  
National Cancer Institute 
NFAT 
nuclear factor of activated T-cells 
NF-kB 
nuclear factor kappa-light-chain-enhancer of activated B-cells 
NHL 
non-Hodgkin lymphomas  
nPR 
nodular partial remission 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction  
PD 
progressive disease; disease progression 
PE 
physical exam 
PFS 
progression-free survival 
  
 
  
 
P-gp 
P-glycoprotein 
PI3K 
phosphoinositide 3-kinase 
PIP3 
phosphatidylinositol 3-phosphate  
PJP 
pneumocystis jiroveci pneumonia 
PK 
pharmacokinetics 
PKC 
protein kinase C 
PLCg2 
phospholipase C gamma 2  
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 130 of 181 
Term 
Definition 
PO 
per os, oral 
PR 
partial remission 
PRBCs 
packed red blood cells 
PR-L 
PR with lymphocytosis 
PRO 
patient-reported outcomes 
PT 
prothrombin time 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 
Q24W 
every 24 weeks 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 
REB 
Research Ethics Board 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
r/r 
relapsed/refractory 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SCT 
stem cell transplantation 
screen 
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SERD 
selective estrogen receptor degrader 
SERM 
selective estrogen receptor modulator 
SFU 
Safety Follow-up  
SJS 
Stevens-Johnson syndrome 
SoA 
Schedule of Assessments 
SPM 
second primary malignancy 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment. 
TEC 
intracellular non-receptor tyrosine kinases 
TEN 
toxic epidermal necrolysis 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum plasma concentration 
TTNT 
time to next treatment 
TTW 
time to worsening 
TXK 
human tyrosine kinase expressed in T-cells that shares sequence identity with TEC family 
kinases and maps to 4p12 
US 
United States 
ULN 
upper limit of normal 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 131 of 181 
Term 
Definition 
WBC 
white blood cells 
WM 
Waldenström’s macroglobulinemia 
WOCBP 
woman of childbearing potential 
XLA 
X-linked agammaglobulinemia 
Xid 
X-linked immunodeficiency 
Y223 
autophosphorylation site within the BTK SH3 domain (Y223 phosphorylation is decisive for 
kinase activity of BTK) 
Y551 
tyrosine residue 551 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 132 of 181 
10.9. 
Appendix 9: Country-Specific Requirements 
The country-specific addenda included in this appendix must be followed in each of the 
respective countries, in addition to all procedures required by the current version of Protocol 
LOXO-BTK-20020. The consolidation of the individual country-specific addenda into this 
appendix is to facilitate transition of this trial to the CTIS system under the new clinical trial 
regulation in the Europian Union (EU).  
All additions have been identified by underline, and deletions have been identified by 
strikethrough. 
10.9.1. 
Belgium 
This addendum includes all revisions to the current global protocol based on feedback from the 
Belgium Regulatory Authority and as outlined in the Belgium Addendum 8.1. Belgium-specific 
changes to the global protocol are presented below. 
10.9.1.1. Protocol Section 5.1 Inclusion Criteria 
[Revised Inclusion Criterion 10 as shown.] 
10. Willingness of men and women of childbearing potential (WOCBP), and their partners, to 
observe barrier and highly effective birth control methods as outlined in Section 10.2 
(Appendix 2), and below, for the duration of treatment and for 6 months following the last 
dose of study treatment or 12 months after the last dose of rituximab, whichever is later. 
When idelalisib is taken with hormonal contraceptives (e.g., birth control pills), 
supplementation with a barrier method is required. 
10.9.1.2. Protocol Section 10.2 Appendix 2: Contraceptive Guidance and Pregnancy 
Information 
[Revised paragraphs 1 and 2 as shown.] 
Willingness of men Men and WOCBP, and their partners, must be willing to observe barrier and 
highly effective birth control methods as outlined below for the duration of treatment and for 
6 months following the last dose of study treatment or 12 months following after the last dose of 
rituximab, whichever is later. 
When idelalisib is taken with hormonal contraceptives (e.g., birth control pills), supplementation 
with a barrier method is required.

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 133 of 181 
10.9.1.3. Protocol Section 1.3.1 Schedule of Assessments for Arm A: Pirtobrutinib Monotherapy 
[Clarified text in the row for bone marrow 
 biopsy, as shown. Only the heading rows and the row containing revisions are 
shown below.] 
Arm A: Pirtobrutinib Monotherapy 
Study 
Period 
Baseline 
Arm A: Pirtobrutinib 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 days 
Day 
1 
Day 8 
(± 3 days) 
Day 1 
(± 7 days) 
Day 1 
(± 7 days) 
+ 7 days 
of last 
dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients 
who 
discontinue 
prior to PD 
Bone 
marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood 
assessment. Optional (required) and to confirm PD (optional) 
• 
 biopsy 
 required at Screening and 
for confirmation of CR  
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 134 of 181 
10.9.2. 
Czech Republic 
This addendum includes all revisions to the current global protocol based on feedback from the 
Czech Republic Regulatory Authority and as outlined in the Czech Republic Addendum 6.1. 
Czech Republic-specific changes to the global protocol are presented below. 
10.9.2.1. Protocol Section 5.1 Inclusion Criteria 
[Revised Inclusion Criterion 10 as shown.] 
10. Willingness of men and women of childbearing potential (WOCBP), and their partners, to 
both observe barrier and/or highly effective birth control methods as outlined in Section 10.2 
(Appendix 2), and below, for the duration of treatment and for 6 months following the last 
dose of study treatment or 12 months after the last dose of rituximab, whichever is later. 
WOCBP are defined as those women following menarche and who are not postmenopausal 
(or 2 years of non-therapy-induced amenorrhea, or surgically sterile). WOCBP must utilize 
highly effective contraception methods as outlined below. In addition, male partners must use 
a barrier method (condoms), observe sexual abstinence, or use sterilization methods such as 
vasectomy, for the duration of treatment and for 6 months following the last dose of study 
treatment or 12 months after the last dose of rituximab, whichever is later. Male patients with 
partners who are WOCBP must use a barrier method (condoms) and their partner must also 
use a highly effective form of contraception as listed below for the duration of treatment and 
for 6 months following the last dose of study treatment or 12 months after the last dose of 
rituximab, whichever is later. 
Highly effective birth control methods with a failure rate of less than 1% per year when 
used consistently and correctly are recommended (Clinical Trial Facilitation Group 
[CTFG 2020]): 
a. Combined estrogen and progestin containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally, or transdermally 
b.  Progestin-only hormonal contraception associated with inhibition of ovulation given 
orally, by injection, or by implant 
c. Intrauterine device (IUD) 
d. Intrauterine hormone-releasing system (IUS) 
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence: Considered a highly effective method only if defined as refraining 
from heterosexual intercourse during an entire period of risk associated with the study 
treatment. The reliability of sexual abstinence will be evaluated in relation to the duration 
of the study and to the usual lifestyle of the patient.  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 135 of 181 
Notes:  
• Women with a history of breast cancer may not use hormone-containing contraception 
(a, b, or d above). One of the other listed methods above should be selected.  
• Women of childbearing potential WOCBP using hormonal contraception methods should 
also use a barrier method as a second form of contraception. 
• Sperm donation and oocyte donation are prohibited during the duration of participation 
on this protocol and for at least 6 months after the last dose of study drug, or at least and 
12 months following last dose of rituximab, whichever is later. 
10.9.2.2. Protocol Section 5.2 Exclusion Criteria 
[Revised Exclusion Criterion 15 as shown.] 
15. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients 
with unknown or negative status are eligible. 
10.9.2.3. Protocol Section 6.5.1 Allowed Concomitant Medication and Supportive Care 
[Revised bullet 6 as shown.] 
• Prophylactic antibiotic or IV immunoglobulin (IVIG) therapy for management of patients 
at risk of infections is recommended. Initiation of antibiotic prophylaxis against 
pneumocystis infection (e.g., with trimethoprim-sulfamethoxazole, dapsone, aerosolized 
pentamidine, or atovaquone) before study drug administration may be warranted and 
should be provided for patients receiving idelalisib, consistent with the idelalisib USPI. 
Local practices or guidelines regarding infection prophylaxis may must be followed. 
10.9.2.4. Protocol Section 8.4.4.8 Pregnancy Testing 
[Revised section as shown.] 
For women of childbearing potential (WOCBP): Pregnancy testing (serum or urine) must be 
conducted at Screening (serum) and at other visits (serum or urine) as outlined in the SoAs 
(Appendix Sections 10.9.2.7, 10.9.2.8, 10.9.2.9, 10.9.2.10, 10.9.2.11, and Section 1.3) or as 
required per local regulations and/or institutional guidelines and may be performed locally. 
Pregnancy reporting guidance is provided in Section 8.5.7. All WOCBP, defined as women who 
are following menarche and who are not postmenopausal (or 2 years of non-therapy-induced 
amenorrhea) or surgically sterile will have a serum or urine pregnancy test at Screening. If any 
urine pregnancy test is positive, study treatment will be delayed until the patient pregnancy status 
is confirmed by a serum pregnancy test. If serum pregnancy test is positive, the patient will be 
permanently discontinued from study treatment. The serum or urine pregnancy tests must be 
performed monthly until 6 months after the last dose in patients receiving pirtobrutinib, 1 month 
after the last dose in patients receiving idelalisib, and 12 months after the last dose in patients 
receiving rituximab, or as required per local regulations and/or institutional guidelines. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 136 of 181 
10.9.2.5. Protocol Section 8.4.4.9 Viral Testing 
[Revised paragraph 2 as shown.] 
Patients with known active CMV infection, a positive HIV test, and/or a history of positive 
HIV test (regardless of CD4 count) are excluded from participation in the trial due to potential 
drug-drug interactions between antiretroviral medications and pirtobrutinib and risk of 
opportunistic infections with both HIV and approved BTK inhibitors. 
10.9.2.6. Protocol Section 10.2 Appendix 2: Contraceptive Guidance and Pregnancy 
Information 
[Revised paragraph 2 as shown.] 
WOCBP are defined as thosewomen following menarche, and who are not postmenopausal 
(or 2 years of non-therapy-induced amenorrhea, or surgically sterile). WOCBP must utilize 
highly effective contraception methods as outlined below. In addition, male partners must use a 
barrier method (condoms) for the duration of treatment and for 6 months following the last dose 
of study treatment or 12 months after the last dose of rituximab, whichever is later. Male patients 
with partners who are WOCBP must use a barrier method (condoms), or observe sexual 
abstinence, or use sterilization methods such as vasectomy, and their partner must also use a 
highly effective form of contraception as listed below for the duration of treatment and for 
6 months following the last dose of study treatment or 12 months after the last dose of rituximab, 
whichever is later.  
[Revised bullet 2 of “Notes” under “Highly effective birth control methods,” as shown.] 
• Women of childbearing potential WOCBP using hormonal contraception methods should 
also use a barrier method as a second form of contraception. Sperm donation and oocyte 
donation are prohibited during the duration of participation on this protocol and for at 
least 6 months after the last dose of study drug, and 12 months following last dose of 
rituximab, whichever is later.

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 137 of 181 
10.9.2.7. Protocol Section 1.3.1 Schedule of Assessments for Arm A: Pirtobrutinib Monotherapy 
[Revised the rows for hematology, hepatitis B/C active disease status and HIV serology, serum or urine pregnancy test, and bone 
marrow 
 biopsy. Only the heading rows and rows containing revisions are shown below.] 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days 
of last 
dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior 
to PD  
Hematology 
X 
X 
X 
X 
C7D1 and 
Q12W 
thereafterX 
X 
X 
X 
• Includes hemoglobin, hematocrit, RBC 
count, WBC count, platelet count, 
percent or absolute differential 
(neutrophils, lymphocytes, eosinophils, 
basophils, and monocytes) 
• Screening results obtained within 3 days 
of C1D1 are acceptable as C1D1 results 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
• On days when hematology is required 
for both safety and response 
assessments, samples should also be 
submitted to the central laboratory 
Hepatitis B/C 
active disease 
status and HIV 
serology 
X 
 
 
 
 
 
 
 
• HBV and HCV testing, and HIV 
serology, to determine if patients have 
active infection 
• Refer to Section 5.2 for exclusions 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 138 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days 
of last 
dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior 
to PD  
Serum or urine 
pregnancy test 
(WOCBP 
only) 
X 
X 
C7D1 and Q12W thereafter  
• Test at Screening should be a serum test 
• Perform within 24 hours of first dose of 
study treatment, and as indicated in table, 
or as required per local regulations and/or 
institutional guidelines 
• Testing should be monthly while 
receiving pirtobrutinib, and testing 
should continue monthly for at least 
6 months from the last dose of 
pirtobrutinib 
• Refer to Section 10.2 Appendix 2 
Bone marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood 
assessment. Optional (required) and Optional to confirm PD (optional) 
• 
 biopsy 
 required at 
Screening and for confirmation of CR  
 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 139 of 181 
10.9.2.8. Protocol Section 1.3.2 Schedule of Assessments for Arm B: Idelalisib plus Rituximab 
[Revised the rows for hepatitis B/C active disease status and HIV serology, serum or urine pregnancy test, and bone marrow 
 
 biopsy. Only the heading rows and rows containing revisions are shown below.] 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 days 
Day 1 
Day 15 
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days 
of last 
dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior to 
PD  
Hepatitis 
B/C active 
disease 
status and 
HIV 
serology 
X 
 
 
 
 
 
 
 
 
 
 
• HBV and HCV testing, and HIV 
serology, to determine if patients 
have active infection 
• Refer to Section 5.2 for exclusions 
Serum or 
urine 
pregnancy 
test 
(WOCBP 
only) 
X 
X 
• Test at Screening should be a 
serum test  
• Perform within 24 hours of first 
dose of study treatment, and as 
indicated in table, or as required 
per local regulations and/or 
institutional guidelines 
• Testing should be monthly while 
receiving idelalisib and/or 
rituximab, and testing should 
continue monthly for at least 
1 month after the last dose of 
idelalisib and 12 months after the 
last dose of rituximab 
• Refer to Section 10.2, Appendix 2 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 140 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 days 
Day 1 
Day 15 
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days 
of last 
dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior to 
PD  
Bone 
marrow 
 
biopsy 
X 
 
 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood 
assessment. Optional (required) and Optional to confirm PD (optional) 
• 
 biopsy 
 required 
at Screening and for confirmation 
of CR  
 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 141 of 181 
10.9.2.9. Protocol Section 1.3.3 Schedule of Assessments for Arm B: Bendamustine plus Rituximab 
[Revised the rows for hepatitis B/C active disease status and HIV serology, and serum or urine pregnancy test. Only the heading rows 
and rows containing revisions are shown below.] 
Arm B: Bendamustine plus Rituximab (BR) 
Study 
Period 
Baseline 
Study Treatment (Cycle = 28 
days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit 
Window 
Up to 28 
days 
Day 1 
Day 2 
Day 1  
(± 3 
days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days (+ 7 
days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) for up 
to 2 years after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who discontinue 
prior to PD 
Hepatitis 
B/C active 
disease 
status and 
HIV 
serology 
X 
 
 
 
 
 
 
 
• HBV and HCV testing, and HIV serology, to 
determine if patients have active infection 
• Refer to Section 5.2 for exclusions 
Serum or 
urine 
pregnancy 
test 
(WOCBP 
only) 
X 
X 
• Test at Screening should be a serum test  
• Perform within 24 hours of first dose of study 
treatment, and as indicated in table, or as 
required per local regulations and/or 
institutional guidelines 
• Testing should be monthly while receiving 
bendamustine and/or rituximab, and testing 
should continue for at least 12 months after 
the last dose of rituximab 
• Refer to Section 10.2 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 142 of 181 
10.9.2.10. Protocol Section 1.3.4 Schedule of Assessments for Optional Crossover Treatment (for Patients Crossing Over from 
Arm B to Arm A) 
[Revised the SoA shown in Section 1.3.4; visit days and procedures have been revised to align with the monotherapy SoA that is 
shown in Section 1.3.1 and Appendix Section 10.9.2.7. The new/revised SoA for optional crossover treatment for the Czech Republic 
is shown below in underscore text; this replaces the SoA shown in Section 1.3.4 in entirety.] 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study 
Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO- Cycles  
2-6 
CO-Cycle 
7+ 
CO-
EOT 
CO-SFU 
CO-
LTFU 
Visit 
Window 
Up to 42 
days 
Day 1 
Day 8  
(±3 days) 
Day 1 
(± 7 days) 
Day 1 
(± 7 days) 
+7 days 
of last 
dose or 
decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
± 4 weeks  
Informed 
consent 
X 
 
 
 
 
 
 
 
• The ICF for crossover must be signed 
before any protocol-specified procedures 
are performed. Refer to Appendix 
Section 10.1.2 
• Crossover screening procedures must be 
completed within 42 days of IRC-
confirmed PD 
Physical 
examination 
X 
X 
X 
X  
CO-C7D1 
and Q12W 
thereafter 
X 
X 
Q12W for 
up to 
2 years 
after last 
dose, 
Q24W 
beyond 
2 years for 
patients 
who 
discontinue 
prior to PD 
• Complete PE includes height (only at 
Screening), weight, basic neurological 
examination and review of relevant 
symptoms at Screening (refer to 
Section 8.4.2) 
• Symptom-directed PE should be limited to 
systems of primary relevance such as 
cardiovascular, respiratory, and those 
associated with tumor assessment (lymph 
nodes, liver, and spleen) and may be 
performed at other timepoints; include 
weight as clinically indicated throughout 
the trial 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 143 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study 
Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO- Cycles  
2-6 
CO-Cycle 
7+ 
CO-
EOT 
CO-SFU 
CO-
LTFU 
Visit 
Window 
Up to 42 
days 
Day 1 
Day 8  
(±3 days) 
Day 1 
(± 7 days) 
Day 1 
(± 7 days) 
+7 days 
of last 
dose or 
decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
± 4 weeks  
• Screening results obtained within 3 days 
of CO-C1D1 are acceptable as CO-C1D1 
results 
ECOG PS 
X 
X 
X 
X  
CO-C7D1 
and Q12W 
thereafter 
X 
X 
 
 
Vital signs 
X 
X 
X 
X  
CO-C7D1 
and Q12W 
thereafter 
X 
X 
 
• Includes systolic and diastolic blood 
pressure, heart rate, respiratory rate, and 
body temperature 
12-lead ECG 
X 
X 
X 
X 
CO-C7D1 
and Q12W 
thereafter 
 
 
 
• Obtain ECGs at specified visits and when 
patients are symptomatic. Refer to 
Section 8.4.3 
• ECGs should be collected: 
− At Screening, single triplicate ECG  
− If an unscheduled ECG is done at any 
time, an electrolyte panel (i.e., calcium, 
magnesium, and potassium) must be 
done to coincide with the ECG 
− If a clinically significant arrhythmia is 
detected, details must be in EDC 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 144 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study 
Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO- Cycles  
2-6 
CO-Cycle 
7+ 
CO-
EOT 
CO-SFU 
CO-
LTFU 
Visit 
Window 
Up to 42 
days 
Day 1 
Day 8  
(±3 days) 
Day 1 
(± 7 days) 
Day 1 
(± 7 days) 
+7 days 
of last 
dose or 
decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
± 4 weeks  
Hematology 
X 
X 
X 
X  
X 
X 
X 
Q24W for 
up to 2 
years after 
last dose 
Q24W 
beyond 2 
years for 
patients 
who 
discontinue 
prior to PD 
• Includes hemoglobin, hematocrit, RBC 
count, WBC count, platelet count, percent 
or absolute differential (neutrophils, 
lymphocytes, eosinophils, basophils, and 
monocytes) 
• Screening results obtained within 3 days 
of C1D1 are acceptable as C1D1 results 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
Blood 
chemistries 
X 
X 
X 
X  
CO-C7D1 
and Q12W 
thereafter 
X 
X 
 
• Blood chemistry from serum or plasma 
should include assessment of: Sodium, 
potassium, chloride, glucose, creatinine, 
total protein, albumin, total bilirubin, 
ALT, and AST 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
• Tests for LDH, calcium, magnesium, 
phosphorus and uric acid are only required 
on Day 1 of CO-C1 
• Screening results within 3 days of CO-
C1D1 are acceptable as CO-C1D1 results 
• Direct (or indirect) bilirubin should be 
performed any time total bilirubin is 
abnormal 
Coagulation 
panel 
X 
As clinically indicated 
 
aPTT and PT (or INR) 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 145 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study 
Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO- Cycles  
2-6 
CO-Cycle 
7+ 
CO-
EOT 
CO-SFU 
CO-
LTFU 
Visit 
Window 
Up to 42 
days 
Day 1 
Day 8  
(±3 days) 
Day 1 
(± 7 days) 
Day 1 
(± 7 days) 
+7 days 
of last 
dose or 
decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
± 4 weeks  
Serum or 
urine 
pregnancy 
test (WOCBP 
only) 
X 
X 
• Test at Screening should be a serum test  
• Perform within 24 hours of first dose of 
study treatment 
• Testing should be monthly, and testing 
should continue for at least 6 months after 
the last dose of pirtobrutinib, 1 month after 
the last dose of idelalisib, and 12 months 
after the last dose of rituximab 
• Refer to Appendix Section 10.2 
Urinalysis 
X 
X 
As clinically indicated 
 
Dipstick analysis is acceptable and should 
include color, specific gravity, pH, glucose, 
bilirubin, occult blood, protein, leukocytes, 
and urobilinogen 
CT or MRI 
X 
 
 
C4D1  
  
CO-C7D1 
and Q12W 
thereafter 
X 
 
Q12W for 
up to 2 
years after 
last dose 
Q24W 
beyond 2 
years for 
patients 
who 
discontinue 
prior to PD 
• Refer to Section 8.3.1 for details. 
• If baseline CT or MRI assessment 
documenting PD by IRC was performed 
within 42 days of planned C1D1, a new 
scan does not need to be obtained 
• All response assessments should occur at 
Q24W intervals relative to CO-C1D1, 
regardless of any treatment delays or 
interruptions 
• At the EOT visit, a repeat CT/MRI does 
not need to be performed if done within 
the proceeding 2 weeks or if PD was 
previously determined 
• Investigator assessment of CT or MRI will 
be done locally at frequency of at least 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 146 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study 
Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO- Cycles  
2-6 
CO-Cycle 
7+ 
CO-
EOT 
CO-SFU 
CO-
LTFU 
Visit 
Window 
Up to 42 
days 
Day 1 
Day 8  
(±3 days) 
Day 1 
(± 7 days) 
Day 1 
(± 7 days) 
+7 days 
of last 
dose or 
decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
± 4 weeks  
Q24W frequency or based on standard of 
care 
Pirtobrutinib 
administration  
 
X 
X 
X 
X 
X 
 
 
• 200 mg PO administered QD (continuous) 
• Crossover treatment should be initiated 
within a window of 42 days after the IRC-
confirmed PD 
• Patient to visit study site Q12W from CO-
C4D1 for dispensation of pirtobrutinib 
• Date of last dose and date of decision to 
end treatment must be recorded in EDC 
prior to patient receiving first dose of 
treatment in crossover 
Patient dosing 
diary 
 
X 
X 
X 
 
 
 
 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 6.5 
Adverse 
events 
X 
X 
X 
X 
X 
X 
X 
 
• Collect SAEs from the time of ICF signing 
through 28 days after the last dose (NCI 
CTCAE v5.0) 
• Collect AEs from the time of dosing 
through SFU; AEs that occur prior to the 
first dose are considered medical history 
unless the AE develops or worsens due to 
study-related procedures 
• All SAEs occurring from the time ICF is 
signed through 28 days after the last dose 
must be reported to Clinical Safety within 
24 hours of knowledge of the event. All 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 147 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study 
Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO- Cycles  
2-6 
CO-Cycle 
7+ 
CO-
EOT 
CO-SFU 
CO-
LTFU 
Visit 
Window 
Up to 42 
days 
Day 1 
Day 8  
(±3 days) 
Day 1 
(± 7 days) 
Day 1 
(± 7 days) 
+7 days 
of last 
dose or 
decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
± 4 weeks  
SAEs that the Investigator considers 
related to study drug occurring after the 
28-day follow-up period must be reported 
to the Sponsor 
• Second primary malignancy (SPM) events 
are to be reported and should continue to 
be reported for up to 5 years from the start 
of pirtobrutinib treatment, regardless of 
seriousness or causal attribution to 
pirtobrutinib treatment 
Survival 
status 
 
X 
X 
X 
X 
X 
X 
Q12W for 
up to 2 
years after 
last dose 
Q24W 
beyond 2 
years 
• Survival information may be collected via 
telephone if no procedures are required; 
survival information should be collected 
approximately Q24W after the SFU visit; 
refer to Section 6.7.5 
• Subsequent anticancer therapy information 
should be collected Q24W after the SFU 
visit until death or study completion 
 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 148 of 181 
10.9.2.11. Protocol Section 1.3.5 Schedule of Assessments for Response Assessments, Arms A and B (Does Not Apply for 
Crossover) 
[Revised the SoA shown in Section 1.3.5; visit days and procedures have been revised to align with the monotherapy SoA that is 
shown in Section 1.3.1 and Appendix Section 10.9.2.7. The new/revised SoA for response assessments is shown below in underscore 
text, and the deleted SoA is shown as strikethrough text; this replaces the SoA shown in Section 1.3.5 in entirety.] 
Response Assessments, Arms A and B (Does Not Apply for Crossover) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 
2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
Days) 
Day 1  
(± 7 
Days) 
 Day 1  
(± 7 Days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 2 
years after 
last dose, 
Q24W 
(± 4 weeks) 
beyond 2 
years for 
patients who 
discontinue 
prior to PD  
Bone marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by 
scan and peripheral blood assessment 
(required) and to confirm PD (optional) 
 
 
• 
 biopsy 
 required at 
Screening and for confirmation of CR  
CT or MRI 
X 
 
 
C4D1 
C7D1 and 
Q12W 
thereafter 
X 
 
X 
• Refer to Section 8.3.1 for details. 
• CT scan with IV contrast agent is the 
preferred method of assessment with 
scans of neck, chest, abdomen and 
pelvis. However, MRI is acceptable if 
CT scan with contrast agent is 
contraindicated 
• All response assessments should occur 
at Q12W intervals relative to C1D1 
regardless of any treatment delays or 
interruptions 
• At the EOT visit, a repeat CT/MRI does 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 149 of 181 
Response Assessments, Arms A and B (Does Not Apply for Crossover) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 
2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
Days) 
Day 1  
(± 7 
Days) 
 Day 1  
(± 7 Days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 2 
years after 
last dose, 
Q24W 
(± 4 weeks) 
beyond 2 
years for 
patients who 
discontinue 
prior to PD  
not need to be performed if done within 
the proceeding 2 weeks or if PD was 
previously determined 
• A central radiology vendor will be used 
to collect and store images for IRC 
review 
Physical 
examination 
X 
 
 
C4D1 
C7D1 and 
Q12W 
thereafter 
X 
 
X 
• Complete PE includes height (only at 
Screening), weight, basic neurological 
examination and review of relevant 
symptoms at Screening (refer to 
Section 8.4.2) 
• Symptom-directed PE should be limited 
to systems of primary relevance such as, 
cardiovascular, respiratory, those 
associated with symptoms, and those 
associated with tumor assessment 
(lymph nodes, liver, and spleen) and 
may be performed at other timepoints; 
include weight as clinically indicated 
throughout the trial 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 150 of 181 
Response Assessments, Arms A and B (Does Not Apply for Crossover) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 
2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 28 
days 
Day 1 
Day 8 
(± 3 
Days) 
Day 1  
(± 7 
Days) 
 Day 1  
(± 7 Days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) 
for up to 2 
years after 
last dose, 
Q24W 
(± 4 weeks) 
beyond 2 
years for 
patients who 
discontinue 
prior to PD  
Hematology 
X 
 
 
C4D1 
Day 1 every 
cycle for 
Arm A, 
C7D1 and 
Q12W 
thereafter for 
Arm B 
X 
 
X 
• Includes hemoglobin, hematocrit, RBC 
count, WBC count, platelet count, 
percent or absolute differential 
(neutrophils, lymphocytes, eosinophils, 
basophils, and monocytes).  
• Screening results obtained within 
3 days of C1D1 are acceptable as C1D1 
results 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
• On days when hematology is required 
for both safety and response 
assessments, samples should also be 
submitted to the central laboratory 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 151 of 181 
10.9.3. 
Germany 
This addendum includes all revisions to the current global protocol based on feedback from the 
German Regulatory Authority and as outlined in the Germany Addendum 7.1. Germany-specific 
changes to the global protocol are presented below.  
10.9.3.1. Protocol Section 5.2 Exclusion Criteria 
[Revised Exclusion Criterion 15 as shown.] 
15. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients 
with unknown or negative status are eligible. 
[Revised Exclusion Criterion 25(c) as shown.] 
25. Patients with the following hypersensitivity: 
c) Prior significant hypersensitivity to rituximab, murine proteins, hyaluronidase, or to any 
of the other excipients (sodium citrate, polysorbate, sodium chloride, sodium hydroxide, 
hydrochloric acid, water for injection) requiring discontinuation or prior allergic or 
anaphylactic reaction to rituximab, murine proteins, hyaluronidase, or to any of the other 
excipients (sodium citrate, polysorbate, sodium chloride, sodium hydroxide, hydrochloric 
acid, water for injection). This does not include manageable infusion-related reaction) 
reactions.  
10.9.3.2. Protocol Section 8.4.4.9 Viral Testing 
[Revised paragraph 2 as shown.] 
Patients with known active CMV infection, a positive HIV test, and/or a history of positive HIV 
test (regardless of CD4 count) are excluded from participation in the trial due to potential drug-
drug interactions between antiretroviral medications and pirtobrutinib and risk of opportunistic 
infections with both HIV and approved BTK inhibitors. 
10.9.3.3. Protocol Section 10.2 Appendix 2: Contraceptive Guidance and Pregnancy 
Information 
[Revised paragraph 1 sentence 1 as shown.] 
Willingness of men and WOCBP, and their partners, must be willing to observe barrier and/or 
highly effective birth control methods as outlined below for the duration of treatment and for 
6 months following the last dose of study treatment or 12 months after the last dose of rituximab, 
whichever is later.0

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 152 of 181 
10.9.3.4. Protocol Section 1.3.1 Schedule of Assessments for Arm A: Pirtobrutinib Monotherapy 
[Revised the rows for hematology, blood chemistries, hepatitis B/C active disease status and HIV serology, serum or urine pregnancy 
test, and bone marrow 
 biopsy. Only the heading rows and rows containing revisions are shown below.] 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Arm A: Pirtobrutinib 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 
2-6 
Cycle 7 
+ 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 days 
Day 1 
Day 8 
(± 3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients who 
discontinue 
prior to PD 
Hematology 
X 
X 
X 
X 
C7D1 and 
Q12W 
Q4W 
thereafter 
X 
X 
X 
• Includes hemoglobin, hematocrit, RBC count, 
WBC count, platelet count, percent or absolute 
differential (neutrophils, lymphocytes, eosinophils, 
basophils, and monocytes) 
• Screening results obtained within 3 days of C1D1 
are acceptable as C1D1 results 
• Repeat testing during Screening is permitted; refer 
to Section 5.5 
• On days when hematology is required for both 
safety and response assessments, samples should 
also be submitted to the central laboratory 
Blood 
chemistries 
X 
X 
X 
X 
C7D1 and 
Q12W 
Q4W 
thereafter 
X 
X 
 
• Blood chemistry from serum or plasma should 
include assessment of: sodium, potassium, chloride, 
glucose, creatinine, total protein, albumin, total 
bilirubin, ALT and AST 
• Repeat testing during Screening is permitted; refer 
to Section 5.5 
• LDH, calcium, magnesium, phosphorus and uric 
acid are required at Screening and Day 1 of C1 to 
C6 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 153 of 181 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Arm A: Pirtobrutinib 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 
2-6 
Cycle 7 
+ 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 days 
Day 1 
Day 8 
(± 3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W 
(± 4 weeks) for 
up to 2 years 
after last dose, 
Q24W 
(± 4 weeks) 
beyond 2 years 
for patients who 
discontinue 
prior to PD 
• Refer to Section 8.4.4.10 for hepatic safety 
monitoring 
• Screening results within 3 days of C1D1 are 
acceptable as C1D1 results 
• Direct (or indirect) bilirubin should be performed 
any time total bilirubin is abnormal 
Hepatitis B/C 
active disease 
status and 
HIV serology 
X 
 
 
 
 
 
 
 
• HBV and HCV testing, and HIV serology, to 
determine if patients have active infection 
• Refer to Section 5.2 for exclusions 
Serum or 
urine 
pregnancy 
test (WOCBP 
only) 
X 
X 
• Perform within 24 hours of first dose of study 
treatment 
• Testing should be monthly while receiving 
pirtobrutinib, and testing should continue monthly 
for at least 6 months from the last dose of 
pirtobrutinib  
• Refer to Section 10.2, Appendix 2 
Serum or 
urine 
pregnancy 
test (WOCBP 
only) 
X 
X 
 
X 
C7D1 and 
Q12W 
thereafter 
 
 
 
• Perform within 24 hours of first dose of study 
treatment, and as indicated in table, or as required 
per local regulations and/or institutional guidelines  
• Refer to Section 10.2, Appendix 2 
Bone marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood 
assessment. Optional (required) and to confirm PD (optional) 
• 
 biopsy 
 required at Screening and 
for confirmation of CR  
 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 154 of 181 
10.9.3.5. Protocol Section 1.3.2 Schedule of Assessments for Arm B: Idelalisib plus Rituximab 
[Revised the rows for 12-lead ECG, hematology, blood chemistries, hepatitis B/C active disease status and HIV serology, serum or 
urine pregnancy test, and bone marrow 
 biopsy. Only the heading rows and rows containing revisions are shown below.] 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period Baseline 
Arm B: IdelaR  
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screenin
g 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 
days 
Day 1 
Day 15 
(± 3 
days) 
Day 1 
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior to 
PD 
12-lead ECG 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
• Obtain ECGs at specified visit 
• Refer to Section 8.4.3 
• At Screening, single ECG 
should be collected 
Hematology 
X 
X 
X 
X 
X 
X 
X 
C7D1 and 
Q12W 
Q4W 
thereafter  
X 
X 
X 
• Includes hemoglobin, 
hematocrit, RBC count, WBC 
count, platelet count, percent or 
absolute differential 
(neutrophils, lymphocytes, 
eosinophils, basophils, and 
monocytes) 
• Screening results obtained 
within 3 days of C1D1 are 
acceptable as C1D1 results 
• Repeat testing during Screening 
is permitted; refer to 
Section 5.5 
• On days when hematology is 
required for both safety and 
response assessments, samples 
should also be submitted to the 
central laboratory 
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 155 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period Baseline 
Arm B: IdelaR  
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screenin
g 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 
days 
Day 1 
Day 15 
(± 3 
days) 
Day 1 
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior to 
PD 
Blood 
chemistries 
X 
X 
X 
X 
X 
X 
X 
C7D1 and 
Q12W 
Q4W 
thereafter 
X 
X 
 
• Blood chemistry from serum or 
plasma should include 
assessment of: sodium, 
potassium, chloride, glucose, 
creatinine, total protein, 
albumin, total bilirubin, ALT, 
and AST 
• Repeat testing during Screening 
is permitted; refer to 
Section 5.5 
• LDH, calcium, magnesium, 
phosphorus and uric acid are 
required at Screening and Day 
1 of C1 to C6 
• Screening results within 3 days 
of C1D1 are acceptable as 
C1D1 results 
Hepatitis 
B/C active 
disease 
status and 
HIV 
serology 
X 
 
 
 
 
 
 
 
 
 
 
• HBV and HCV testing, and 
HIV serology, to determine if 
patients have active infection 
• Refer to Section 5.2 for 
exclusions 
Serum or 
urine 
pregnancy 
test 
X 
X 
 
X 
 
X 
 
X  
• Perform within 24 hours of first 
dose of study treatment 
• Testing should be monthly 
while receiving idelalisib 
and/or rituximab, and testing 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 156 of 181 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period Baseline 
Arm B: IdelaR  
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screenin
g 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 
7+ 
EOT 
SFU 
LTFU 
Visit 
Window 
Up to 
28 
days 
Day 1 
Day 15 
(± 3 
days) 
Day 1 
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior to 
PD 
(WOCBP 
only) 
should continue monthly for at 
least 1 month after the last dose 
of idelalisib and 12 months 
after the last dose of rituximab 
• Refer to Section 10.2, 
Appendix 2 
Serum or 
urine 
pregnancy 
test 
(WOCBP 
only) 
X 
X 
 
X 
 
X 
 
 C7D1 and 
Q12W 
thereafter  
 
 
 
Perform within 24 hours of first 
dose of study treatment, and as 
indicated in table, or as 
required per local regulations 
and/or institutional guidelines 
Refer to Section 10.2, Appendix 2 
Bone 
marrow 
 
biopsy 
X 
 
 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood 
assessment. Optional (required) and to confirm PD (optional) 
• 
 biopsy 
 
required at Screening and for 
confirmation of CR  
 
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 157 of 181 
10.9.3.6. Protocol Section 1.3.3 Schedule of Assessments for Arm B: Bendamustine plus Rituximab 
[Revised the rows for 12-lead ECG, hepatitis B/C active disease status and HIV serology, and serum or urine pregnancy test. Only the 
heading rows and rows containing revisions are shown below.] 
Arm B: Bendamustine plus Rituximab (BR) 
Study 
Period 
Baseline 
Arm B: BR  
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
EOT 
SFU 
LTFU 
 
Visit 
Window 
Up to 
28 days 
Day 1 
Day 2 
Day 1 
(± 3 days) 
Day 2 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) for up 
to 2 years after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who discontinue 
prior to PD 
12-lead ECG 
X 
X 
 
X 
 
X 
 
 
• Obtain ECGs at specified visit 
• Refer to Section 8.4.3 
• At Screening, single ECG should be 
collected 
Hepatitis B/C 
active disease 
status and 
HIV serology 
X 
 
 
 
 
 
 
 
• HBV and HCV testing, and HIV 
serology, to determine if patients have 
active infection  
• Refer to Section 5.2 for exclusions 
Serum or 
urine 
pregnancy 
test (WOCBP 
only) 
X 
X 
 
X 
 
X 
• Perform within 24 hours of first dose 
of study treatment 
• Testing should be monthly while 
receiving bendamustine and/or 
rituximab, and testing should continue 
for at least 12 months after the last 
dose of rituximab 
• Refer to Section 10.2, Appendix 2 
Serum or 
urine 
pregnancy 
test (WOCBP 
only) 
X 
X 
 
X 
 
X 
 
 
Perform within 24 hours of first dose of 
study treatment, and as indicated in 
table, or as required per local 
regulations and/or institutional 
guidelines 
Refer to Section 10.2, Appendix 2 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 158 of 181 
10.9.3.7. Protocol Section 1.3.4 Schedule of Assessments for Optional Crossover Treatment (for Patients Crossing Over from 
Arm B to Arm A) 
[Revised the SoA shown in Section 1.3.4; visit days and procedures have been revised to align with the monotherapy SoA that is 
shown in Section 1.3.1 and Appendix Section 10.9.3.4. The new/revised SoA for optional crossover treatment for the Czech Republic 
is shown below in underscore text; this replaces the SoA shown in Section 1.3.4 in entirety.]  
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO-
Cycles 
2-6 
CO-
Cycle 7+ 
CO-EOT 
CO-SFU 
CO-LTFU 
Visit Window 
Up to 
42 days 
Day 1 
Day 8  
(±3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+14 days 
of last dose 
or decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W for up to 2 years 
after last dose 
Q24W beyond 2 years 
for patients who 
discontinue prior to PD 
(± 4 weeks)  
Informed 
consent 
X 
 
 
 
 
 
 
 
• The ICF for crossover must be signed 
before any protocol-specified procedures 
are performed. Refer to Section 10.1.2, 
Appendix 1 
• Crossover screening procedures must be 
completed within 42 days of 
IRC-confirmed PD 
Physical 
examination 
X 
X 
X 
X 
CO-
C7D1 
and 
Q12W 
thereafter 
X 
X 
X 
• Complete PE includes height (only at 
Screening), weight, basic neurological 
examination and review of relevant 
symptoms at Screening (refer to 
Section 8.4.2) 
• Symptom-directed PE should be limited to 
systems of primary relevance such as, 
cardiovascular, respiratory, and those 
associated with tumor assessment (lymph 
nodes, liver, and spleen) and may be 
performed at other timepoints; include 
weight as clinically indicated throughout 
the trial 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 159 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO-
Cycles 
2-6 
CO-
Cycle 7+ 
CO-EOT 
CO-SFU 
CO-LTFU 
Visit Window 
Up to 
42 days 
Day 1 
Day 8  
(±3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+14 days 
of last dose 
or decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W for up to 2 years 
after last dose 
Q24W beyond 2 years 
for patients who 
discontinue prior to PD 
(± 4 weeks)  
• Screening results obtained within 3 days of 
CO-C1D1 are acceptable as CO-C1D1 
results 
ECOG PS 
X 
X 
X 
X 
CO-
C7D1 
and 
Q12W 
thereafter 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
CO-
C7D1 
and 
Q12W 
thereafter 
X 
X 
 
• Includes systolic and diastolic blood 
pressure, heart rate, respiratory rate and 
body temperature 
Results of tests in the section below are required for crossover eligibility determination 
12-lead ECG 
X 
X  
X 
X 
CO-
C7D1 
and 
Q12W 
thereafter 
X 
 
 
• Obtain ECGs at specified visits and when 
patients are symptomatic. Refer to 
Section 8.4.3 
• ECGs should be collected: 
− At Screening, single ECG  
− If an unscheduled ECG is done at any 
time, an electrolyte panel (i.e., calcium, 
magnesium, and potassium) must be 
done to coincide with the ECG 
− If a clinically significant arrhythmia is 
detected, details must be entered in the 
EDC 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 160 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO-
Cycles 
2-6 
CO-
Cycle 7+ 
CO-EOT 
CO-SFU 
CO-LTFU 
Visit Window 
Up to 
42 days 
Day 1 
Day 8  
(±3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+14 days 
of last dose 
or decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W for up to 2 years 
after last dose 
Q24W beyond 2 years 
for patients who 
discontinue prior to PD 
(± 4 weeks)  
Hematology 
X 
X 
X 
X 
CO-
C7D1 
and 
Q4W 
thereafter 
X 
X 
X 
• Includes hemoglobin, hematocrit, RBC 
count, WBC count, platelet count, percent 
or absolute differential (neutrophils, 
lymphocytes, eosinophils, basophils, and 
monocytes) 
• Screening results obtained within 3 days of 
C1D1 are acceptable as C1D1 results 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
Blood 
chemistries 
X 
X 
X 
X 
CO-
C7D1 
and 
Q4W 
thereafter 
X 
X 
 
• Blood chemistry from serum or plasma 
should include assessment of: Sodium, 
potassium, chloride, glucose, creatinine, 
total protein, albumin, total bilirubin, ALT, 
and AST 
• Repeat testing during Screening is 
permitted; refer to Section 5.5 
• LDH, calcium, magnesium, phosphorus and 
uric acid are only required on Day 1 of 
CO-C1 
• Screening results within 3 days of CO-
C1D1 are acceptable as CO-C1D1 results 
• Direct (or indirect) bilirubin should be 
performed any time total bilirubin is 
abnormal 
Coagulation 
panel 
X 
As clinically indicated 
 
aPTT and PT (or INR) 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 161 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO-
Cycles 
2-6 
CO-
Cycle 7+ 
CO-EOT 
CO-SFU 
CO-LTFU 
Visit Window 
Up to 
42 days 
Day 1 
Day 8  
(±3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+14 days 
of last dose 
or decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W for up to 2 years 
after last dose 
Q24W beyond 2 years 
for patients who 
discontinue prior to PD 
(± 4 weeks)  
Serum or urine 
pregnancy test 
(WOCBP only) 
X 
X 
• Perform within 24 hours of first dose of 
study treatment 
• Testing should be monthly while receiving 
pirtobrutinib and continue monthly for at 
least 6 months after the last dose of 
pirtobrutinib  
• Refer to Appendix Section 10.2 
Urinalysis 
X 
X 
As clinically indicated 
 
Dipstick analysis is acceptable and should 
include color, specific gravity, pH, glucose, 
bilirubin, occult blood, protein, leukocytes, 
and urobilinogen 
Documentation or sampling of the following are required during Screening, but results not required prior to initiation of pirtobrutinib 
CT or MRI 
X 
 
 
C4D1 
CO-
C7D1 
and 
Q12W 
thereafter 
X 
 
X 
• Refer to Section 8.1 for details. 
• If baseline CT or MRI assessment 
documenting PD by IRC was performed 
within 42 days of planned C1D1, a new 
scan does not need to be obtained 
• All response assessments should occur at 
Q12W intervals relative to CO-C1D1, 
regardless of any treatment delays or 
interruptions 
• At the EOT visit, a repeat CT/MRI does not 
need to be performed if done within the 
preceding 2 weeks or if PD was previously 
determined 
• Investigator assessment of CT or MRI will 
be done locally at frequency of at least 
Q12W frequency or based on standard of 
care 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 162 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO-
Cycles 
2-6 
CO-
Cycle 7+ 
CO-EOT 
CO-SFU 
CO-LTFU 
Visit Window 
Up to 
42 days 
Day 1 
Day 8  
(±3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+14 days 
of last dose 
or decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W for up to 2 years 
after last dose 
Q24W beyond 2 years 
for patients who 
discontinue prior to PD 
(± 4 weeks)  
Pirtobrutinib 
administration  
 
X 
X 
X 
X 
X 
 
 
• 200 mg PO administered QD (continuous) 
• Crossover treatment should be initiated 
within a window of 42 days after the 
IRC-confirmed PD 
• Patient to visit study site Q12W from 
CO-C4D1 for dispensation of pirtobrutinib 
• Date of last dose and date of decision to end 
treatment must be recorded in EDC prior to 
patient receiving first dose of treatment in 
crossover. 
Patient dosing 
diary 
 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
medication 
 
X 
X 
X 
X 
X 
X 
 
Refer to Section 6.5 
Adverse events 
 
X 
X 
X 
X 
X 
X 
 
• Collect SAEs from the time of ICF signing 
through 28 days after the last dose (NCI 
CTCAE v5.0) 
• Collect AEs from the time of dosing 
through SFU; AEs that occur prior to the 
first dose are considered medical history 
unless the AE develops or worsens due to 
study-related procedures 
• All SAEs occurring from the time ICF is 
signed through 28 days after the last dose 
must be reported to Clinical Safety within 
24 hours of knowledge of the event. All 
SAEs that the Investigator considers related 
to study drug occurring after the 28-day 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 163 of 181 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-Cycle 1 
CO-
Cycles 
2-6 
CO-
Cycle 7+ 
CO-EOT 
CO-SFU 
CO-LTFU 
Visit Window 
Up to 
42 days 
Day 1 
Day 8  
(±3 
days) 
Day 1 
(± 7 
days) 
Day 1 
(± 7 
days) 
+14 days 
of last dose 
or decision 
to 
terminate 
treatment 
28 days 
 (+ 7 days) after 
last dose or 
decision to 
terminate 
treatment 
Q12W for up to 2 years 
after last dose 
Q24W beyond 2 years 
for patients who 
discontinue prior to PD 
(± 4 weeks)  
follow-up period must be reported to the 
Sponsor 
• Second primary malignancy (SPM) events 
are to be reported and should continue to be 
reported for up to 5 years from the start of 
pirtobrutinib treatment, regardless of 
seriousness or causal attribution to 
pirtobrutinib treatment 
Survival status 
 
X 
X 
X 
X 
X 
X 
X 
• Survival information may be collected via 
telephone if no procedures are required; 
survival information should be collected 
approximately Q24W after the SFU visit; 
refer to Section 6.7.5 
• Subsequent anticancer therapy information 
should be collected Q24W after the SFU 
visit until death or study completion 
 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 164 of 181 
10.9.3.8. Protocol Section 1.3.5 Schedule of Assessments for Response Assessments, Arms A and B (Does Not Apply for 
Crossover) 
[Revised the “NOTE,” as shown.] 
NOTE: This section is a guide to specify elements required for response assessment without duplicating activities in the SoAs above. 
Assessments should include disease and symptom-focused directed physical examination, imaging, and hematology results and bone 
marrow examinations as described in iwCLL 2018. 
[Revised the SoA rows for bone marrow 
 biopsy, CT or MRI, physical examination, and hematology. Only the heading 
rows and rows containing revisions are shown below.]  
Response Assessments, Arms A and B (Does Not Apply for Crossover) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 +  
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1  
(± 7 Days) 
+ 7 days of last 
dose or decision 
to terminate 
treatment 
28 days 
 (+ 7 days) after last 
dose or decision to 
terminate treatment 
Q12W (± 4 weeks) for up 
to 2 years after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who discontinue 
prior to PD 
Bone marrow 
 
biopsy 
X 
Within 4-8 weeks of confirmed CR 
by scan and peripheral blood 
assessment. Optional (optional) and 
to confirm PD (required) 
 
 
• 
 biopsy 
 required at Screening 
and for confirmation of CR  
 
CT or MRI 
X 
C4D1, C7D1, and 
Q12W thereafter 
X 
 
X 
• Refer to Section 8.3.1 for details 
• CT scan with IV contrast agent is the preferred 
method of assessment with scans of neck, 
chest, abdomen, and pelvis. However, MRI is 
acceptable if CT scan with contrast agent is 
contraindicated 
• All response assessments should occur at 
Q12W intervals relative to C1D1 regardless of 
any treatment delays or interruptions 
• At the EOT visit, a repeat CT/MRI does not 
need to be performed if done within the 
proceeding 2 weeks or if PD was previously 
determined 
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 165 of 181 
Response Assessments, Arms A and B (Does Not Apply for Crossover) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 +  
EOT 
SFU 
LTFU 
 
Visit Window 
Up to 
28 days 
Day 1  
(± 7 Days) 
+ 7 days of last 
dose or decision 
to terminate 
treatment 
28 days 
 (+ 7 days) after last 
dose or decision to 
terminate treatment 
Q12W (± 4 weeks) for up 
to 2 years after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who discontinue 
prior to PD 
• A central radiology vendor will be used to 
collect and store images for IRC review 
Physical 
Examination 
X 
C4D1, C7D1, and 
Q12W thereafter 
X 
 
X 
• Complete PE includes height (only at 
Screening), weight, basic neurological 
examination, and review of relevant symptoms 
at Screening; refer to Section 8.4.2 
• Symptom-directed PE should be limited to 
systems of primary relevance such as 
cardiovascular, respiratory, those associated 
with symptoms, and those associated with 
tumor assessment (lymph nodes, liver, and 
spleen) and may be performed at other 
timepoints; include weight as clinically 
indicated throughout the trial 
Hematology 
X 
C4D1, C7D1, and 
Q12W thereafter 
X 
 
X 
• Includes hemoglobin, hematocrit, RBC count, 
WBC count, platelet count, percent or absolute 
differential (neutrophils, lymphocytes, 
eosinophils, basophils, and monocytes) 
• Screening results obtained within 3 days of 
C1D1 are acceptable as C1D1 results 
• Repeat testing during Screening is permitted; 
refer to Section 5.5 
• On days when hematology is required for both 
safety and response assessments, samples 
should also be submitted to the central 
laboratory 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 166 of 181 
10.9.4. 
France 
This addendum includes all revisions to the current global protocol based on feedback from the 
French Regulatory Authority and as outlined in the France Addendum 5.0. France-specific 
changes to the global protocol are presented below. 
10.9.4.1. Protocol Section 5.1 Inclusion Criteria 
[Added new Inclusion Criterion 5 as shown. Revised numbering of Inclusion Criteria 5 through 
10 (now numbered as 6 through 11).] 
5. Patients with 17p deletion must have received prior venetoclax or be ineligible for treatment 
with venetoclax. 
[Revised sentence 1 of Inclusion Criterion 11 as shown.] 
11. Willingness of men and women of childbearing potential (WOCBP), and their partners, to 
both observe barrier and/or highly effective birth control methods as outlined in Protocol 
Section 10.2 (Protocol Appendix 2 and below) for the duration of treatment and for 6 months 
following the last dose of study treatment or 12 months after the last dose of rituximab, 
whichever is later.  
10.9.4.2. Protocol Section 5.2 Exclusion Criteria 
[Added new Exclusion Criterion 24 as shown. Revised numbering of Exclusion Criteria 24 
and 25 (now numbered as 25 and 26).] 
24. Patients who have been pretreated with IdelaR or BR and had either documented PD as 
determined by the Investigator, or could not tolerate the regimen, should not be retreated with 
the same regimen. 
[Added new Exclusion Criteria 27 and 28 as shown.] 
27. Patients with progressive multifocal leukoencephalopathy (PML) or history thereof. 
28. Patients with medical conditions which, at the Investigator’s discretion, would preclude the 
use of both comparator treatments. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 167 of 181 
10.9.4.3. Protocol Section 6.6.1 Dose Modifications and Toxicity Management Guidelines 
for Arm A: Pirtobrutinib 
[Revised Table 6.3 heading row and “First occurrence” row as shown.] 
Adverse Events 
Occurrences 
Requiring Dose 
Modification 
ARM A 
(Pirtobrutinib) 
Dose 
Modification 
(Starting dose 
200 mg QD) 
ARM A (Pirtobrutinib) Modification / 
Instructions 
• Grade 3 or greater non-
hematologic toxicity a,  
• Grade 3 neutropenia with 
fever and/or infection, 
• Grade 4 neutropenia 
lasting ≥ 7 days,  
• Grade 3 thrombocytopenia 
with bleeding, or 
• Grade 4 thrombocytopenia 
First 
occurrence 
No change 
Hold pirtobrutinib until recovery to 
Grade 1 or baseline; may restart at original 
reduce by a dose level (200 to 100 mg 
QD) 
Second 
occurrence 
100 mg QD 
Hold pirtobrutinib until recovery to 
Grade 1 or baseline; may restart at one 
dose level lower (100 mg QD) b 
Third 
occurrence 
50 mg QD 
Hold pirtobrutinib until recovery to 
Grade 1 or baseline; may restart at one 
dose level lower (50 mg QD) 
Fourth 
occurrence 
Discontinue 
Discontinue  
a   For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification 
recommendations should be implemented if patients experience an increase of ≥ 3× baseline AST or ALT, 
or an AST or ALT increase of ≥ 2× baseline with concurrent total bilirubin ≥ 2× ULN. 
b   If dose was reduced at first occurrence, reduce by an additional dose level if subsequent events occur. 
10.9.4.4. Protocol Section 10.2 Appendix 2: Contraceptive Guidance and Pregnancy 
Information 
[Revised paragraph 1 sentence 1 as shown.] 
Willingness of men and WOCBP, and their partners, to observe barrier and/or highly effective 
birth control methods as outlined below for the duration of treatment and for 6 months following 
the last dose of study treatment or 12 months after the last dose of rituximab, whichever is later.

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 168 of 181 
10.9.4.5. Protocol Section 1.3.1 Schedule of Assessments for Arm A: Pirtobrutinib Monotherapy 
[Revised the row for bone marrow 
 biopsy; only the heading rows and the row containing revisions are shown below.] 
Arm A: Pirtobrutinib Monotherapy 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycles 2-6 
Cycle 7 + 
EOT 
SFU 
LTFU 
Visit Window Up to 28 days 
Day 1 
Day 8 
(± 3 days) 
Day 1  
(± 7 days) 
 Day 1  
(± 7 days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) for 
up to 2 years after last 
dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior to PD  
Bone marrow 
 
biopsy 
X 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood assessment. 
Optional (required) and Optional to confirm PD (optional) 
• 
 biopsy 
 required 
at Screening and for 
confirmation of CR  
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 169 of 181 
10.9.4.6. Protocol Section 1.3.2 Schedule of Assessments for Arm B: Idelalisib plus Rituximab 
[Added a row for triglycerides; revised the row for bone marrow 
 biopsy; only the heading rows and the rows containing 
revisions are shown below.] 
Arm B: Idelalisib plus Rituximab (IdelaR) 
Study Period 
Baseline 
Study Treatment (Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7+ 
EOT 
SFU 
LTFU 
Visit 
Window 
 Up to 
28 days 
Day 
1 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15  
(± 3 
days) 
Day 1  
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 1 
(± 7 
days) 
+ 7 days of 
last dose or 
decision to 
terminate 
treatment 
28 days 
(+ 7 days) 
after last 
dose or 
decision to 
terminate 
treatment 
Q12W (± 4 weeks) 
for up to 2 years 
after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who 
discontinue prior to 
PD  
Triglycerides 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
• On C1D1, testing must 
occur predose since this will 
be used as the baseline 
value for monitoring 
Bone marrow 
 
biopsy 
X 
 
 
 
 
Within 4-8 weeks of confirmed CR by scan and peripheral blood 
assessment. Optional (required) and Optional to confirm PD (optional) 
• 
 biopsy 
 
required at Screening and 
for confirmation of CR  
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 170 of 181 
10.9.4.7. Protocol Section 1.3.4 Schedule of Assessments for Optional Crossover Treatment (for Patients Crossing Over from 
Arm B to Arm A) 
[Revised the row for CT or MRI, and the row for survival status, as shown; only the heading rows and rows containing revisions are 
shown below.] 
Optional Crossover Treatment (for Patients Crossing Over from Arm B to Arm A) 
Study 
Period 
Baseline 
Study Treatment  
(Cycle = 28 days) 
Post-Study Treatment 
Discontinuation 
Instructions 
Evaluation 
CO-
Screening 
CO-
Cycle 1 
CO-Cycle 
4 and 
higher 
CO-EOT 
CO-SFU 
CO-
LTFU 
Visit 
Window 
Up to 42 
days 
Day 1 
± 14 Days 
+14 days 
of last 
dose or 
decision to 
terminate 
treatment 
28 days 
 (+ 7 days) 
after last dose 
or decision to 
terminate 
treatment 
Q24W (± 4 
weeks)  
CT or MRI 
X 
 
CO-C7D1 
and Q24W 
thereafter 
X 
 
X Q24W 
for up to 
2 years after 
last dose 
Q24W 
beyond 
2 years 
• Refer to Section 8.1 for details. 
• If baseline CT or MRI assessment documenting PD by IRC was 
performed within 42 days of planned C1D1, a new scan does not 
need to be obtained 
• All response assessments should occur at Q24W intervals relative 
to CO-C1D1, regardless of any treatment delays or interruptions 
• At the EOT visit, a repeat CT/MRI does not need to be performed 
if done within the proceeding 2 weeks or if PD was previously 
determined 
• Investigator assessment of CT or MRI will be done locally at 
frequency of at least Q24W frequency or based on standard of care 
Survival 
status 
 
X 
X 
X 
X 
X Q24W 
for up to 
2 years after 
last dose 
Q24W 
beyond 
2 years 
• Survival information may be collected via telephone if no 
procedures are required; survival information should be collected 
approximately Q24W after the SFU visit; refer to Section 6.7.5 
• Subsequent anticancer therapy information should be collected 
Q24W after from the end of SFU visit for the first 2 years after 
discontinuation from study treatment and approximately Q24W 
thereafter until death or study completion 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
Version 6.2 
Confidential & Proprietary 
Page 171 of 181 
10.9.4.8. Protocol Section 1.3.5 Schedule of Assessments for Response Assessments, Arms A and B (Does Not Apply for 
Crossover) 
[Revised the row for bone marrow 
biopsy; only the heading rows and the row containing revisions are shown below.] 
Response Assessments, Arms A and B (Does Not Apply for Crossover) 
Study Period 
Baseline 
Study Treatment 
(Cycle = 28 days) 
Post-Study Treatment Discontinuation 
Instructions 
Evaluation 
Screening 
Cycle 1 +  
EOT 
SFU 
LTFU 
 
Visit 
Window 
Up to 28 
days 
Day 1  
(± 7 Days) 
+ 7 days of last 
dose or decision 
to terminate 
treatment 
28 days 
 (+ 7 days) after last 
dose or decision to 
terminate treatment 
Q12W (± 4 weeks) for up 
to 2 years after last dose, 
Q24W (± 4 weeks) 
beyond 2 years for 
patients who discontinue 
prior to PD 
Bone marrow 
 
biopsy 
X 
Within 4-8 weeks of confirmed CR by 
scan and peripheral blood assessment. 
Optional (required) and to confirm PD 
(optional) 
 
 
• 
 biopsy 
 required at Screening 
and for confirmation of CR  
 
CCI
CCI
CCI
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 172 of 181 
10.10. 
Appendix 10: Exceptional Circumstances: Provisions for Changes 
in Study Conduct During Exceptional Circumstances 
10.10.1. 
Purpose for Appendix 
This appendix includes specific changes to the global protocol that are allowed under exceptional 
circumstances as outlined in Protocol Addendum 3.0 and as presented below. 
Implementation of this Appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the Sponsor in partnership with the 
Investigator. 
Exceptional Circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
Investigators, patients, or both to attend onsite visits or to conduct planned study procedures. 
Implementing Changes under Exceptional Circumstances 
In an exceptional circumstance, after receiving the Sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
IRBs/IECs, regulatory bodies and any other relevant local authorities, as required, will be 
notified as early as possible to communicate implementation of changes in study conduct due to 
exceptional circumstances. To protect the safety of study patients, urgent changes may be 
implemented before such communications are made, but all changes will be reported as soon as 
possible following implementation. If approval by IRBs/IECs, regulatory bodies, or both is 
required per local regulations, confirmation of this approval will be retained in the study records. 
In the event written approval is granted by the Sponsor for changes in study conduct, additional 
written guidance, if needed, will be provided by the Sponsor. 
Considerations for Making a Change 
The prevailing consideration for making a change is ensuring the safety of study patients. 
Additional important considerations for making a change are compliance with GCP, enabling 
patients to continue safely in the study and maintaining the integrity of the study. The allowances 
made herein have taken into consideration the risk:benefit of the patient population with regard 
to their study disease diagnosis and presumed impact that these changes would have on patient 
safety and study integrity. 
Informed Consent 
Additional consent from the patient will be obtained, if required, for: 
• Participation in remote visits, as defined in Section “Remote Visits,” 
• A change in the method, location, or both, of study intervention administration,  
• Dispensation of additional study intervention during an extended treatment period,  

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 173 of 181 
• Alternate delivery of study intervention and ancillary supplies, and 
• Provision of their personal or medical information required prior to implementation of 
these activities. 
10.10.2. 
Specific Changes to this Protocol 
This is the Exceptional Circumstance Addendum to Protocol LOXO-BTK-20020. The purpose 
of this addendum is to allow temporary flexibility in study visits, assessments, and study drug 
dispensation as a result of the COVID-19 pandemic or other exceptional circumstances. 
Changes in Study Conduct During Exceptional Circumstances 
Changes in study conduct not described in this addendum, or not consistent with applicable local 
regulations, are not allowed. 
The changes in study conduct that are discussed within this addendum will not be considered 
protocol deviations. 
10.10.2.1. Remote Visits 
In source documents and the electronic Case Report Form (eCRF), the study site should capture 
the visit location and method, with a specific explanation that includes the term “COVID-19 
related” (when applicable) for any data missing because of missed in-person site visits. 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, but 
are not limited to, concomitant medications, review of systems, Eastern Cooperative 
Oncology Group (ECOG) performance status, dosing information, patient-reported outcome 
measures, and information regarding local healthcare utilization/hospitalization.  
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when patients cannot travel to the site due to an 
exceptional circumstance, if written approval is provided by the Sponsor. Procedures 
performed at such visits include, but are not limited to, review of systems, physical exams, 
and laboratory studies (e.g., hematology, chemistry, etc.).  
Other alternative locations: Other procedures that may be done at an alternate location in 
exceptional circumstances include, but are not limited to, review of systems, physical exam, 
ECG tracings, laboratory studies (e.g., hematology, chemistry), and radiologic imaging.  
• Regardless of the type of remote visits implemented, the protocol requirements regarding 
the reporting of adverse events (AEs), serious adverse events (SAEs), and product 
complaints remain unchanged. Furthermore, every effort should be made to enable 
patients to return to onsite visits as soon as reasonably possible, while ensuring the safety 
of both the patients and the site staff. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 174 of 181 
10.10.2.2. Local Laboratory Testing Option 
Local laboratory testing may be conducted in lieu of central laboratory testing (refer to 
Appendix Section 10.10.4). The local laboratory must be qualified in accordance with applicable 
local regulations. 
10.10.2.3. Study Intervention, Ancillary Supplies, and Patient Diaries 
When a patient is unable to go to the site to receive study supplies during normal onsite visits, 
the site should work with the Sponsor to determine appropriate actions. These actions may 
include:  
• Asking the patient to go to the site and receive study supplies from site staff without 
completion of a full study visit,  
• Asking the patient’s designee to go to the site and receive study supplies on a patient’s 
behalf, and 
• Arranging delivery of study supplies 
These requirements must be met before action is taken: 
• Alternate delivery of study intervention should be performed in a manner that ensures 
product integrity. The existing protocol requirements for product accountability remain 
unchanged, including verification of patient’s receipt of study supplies. 
• When delivering supplies to a location other than the study site (for example, patient’s 
home), the Investigator, Sponsor, or both should ensure oversight of the shipping process 
to ensure accountability and product quality (that is, storage conditions maintained and 
intact packaging upon receipt). 
• Instructions may be provided to the patient or designee on the final disposition of any 
unused or completed study supplies. 
10.10.3. 
Documentation 
In source documents, the site should document the patient’s verbal understanding and agreement 
for having visits at an alternative location due to exceptional circumstances. Additionally, the 
study site should capture in source documents both the alternative visit location and method. Any 
local laboratory or imaging/diagnostic center used for sample or data collection should comply 
with local regulations. 
Changes to study conduct must be documented as follows: 
• Sites will identify and document within source records the details of how patients, visit 
types, and conducted activities were affected by exceptional circumstances. 
• Dispensing/shipment records of study intervention and relevant communications, 
including delegation, should be filed with site study records. 
Source documents generated at a location other than the study site should be part of the 
Investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 175 of 181 
10.10.4. 
Tabular Summary of Changes in this Appendix 
Visit or 
Assessment  
Protocol  
Protocol Addendum 3.0 
Study visits 
Performed in-person at study site 
May be conducted at other (local) healthcare 
facilities, by home visits or telemedicine 
(except Screening, C1D1 for patients on Arm 
A, Cycles 1-6 for patients on Arm B, and 
crossover [CO]-C1D1). 
Physical 
examination, vital 
signs, and ECOG 
PS 
Performed at study site during every 
study visit 
After Screening, should be performed at least 
every other cycle through C7D1. May be 
conducted at remote (local) healthcare 
facilities. Home blood pressure, heart rate and 
temperature monitoring may be performed. 
ECGs 
Performed at study site at Screening, 
then as listed on Schedules of 
Assessments (SoAs) (Section 1.3) 
May be conducted at remote (local) healthcare 
facilities. 
Patient may take study drug at home and await 
dose-timed electrocardiogram (ECG) capture 
to reduce time in clinic. 
Blood draws  
Performed at study site at Screening, 
then as listed on SoAs (Section 1.3) 
May be conducted at remote (local) or 
commercial laboratories (except at C1D1 for 
patients on Arm A, Cycles 1-6 for patients on 
Arm B, and CO-C1D1). 
Serum or urine 
pregnancy tests 
(WOCBP only) 
Performed at study site at Screening, 
then as listed on SoAs (Section 1.3) 
May be conducted at remote (local) or 
commercial laboratories. 
Urinalysis 
Performed at study site at Screening, 
then as listed on SoAs (Section 1.3) 
May be conducted at remote (local) or 
commercial laboratories at Screening, then 
may be performed as clinically indicated. 
Bone marrow 
 
biopsy 
Collected at study site Screening, at 
visit days listed on SoAs 
(Section 1.3), and at End of 
Treatment (EOT) 
Inability to obtain EOT post-progression 
tumor sample(s) will not be considered a 
protocol deviation. 
CT or MRI 
radiological 
imaging 
Performed at study site at visit days 
listed on SoAs (Section 1.3) 
May be conducted at remote (local) healthcare 
facilities at visit days listed on SoAs (Protocol 
Section 1.3), with provision of ability to 
provide images to central imaging vendor.  
CCI
CCI

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 176 of 181 
Visit or 
Assessment  
Protocol  
Protocol Addendum 3.0 
Dispense study 
drug (oral agents 
only) 
No more than 1 cycle is dispensed at 
study site for Arm A and Arm B 
patients 
May be shipped directly to patients, and more 
than 1 cycle may be dispensed at a time with 
Sponsor approval.  
Note: It is the Investigator’s responsibility to 
determine if the patient is deemed medically 
fit to receive more than 1 cycle of study drug 
at a time and/or if drug should be shipped 
directly to the patient. Once this is determined 
by the Investigator, sites still need to seek 
Sponsor approval for the shipment of study 
drug directly to the patient. 
10.10.5. 
Changes in Protocol Section 1.3: Schedule of Assessments 
Visits and assessments may be changed as outlined above in Appendix Section 10.10.2. 
Additional guidance is provided for remote visits (Appendix Section 10.10.2.1), local laboratory 
testing (Appendix Section 10.10.2.2), and study intervention and supplies 
(Appendix Section 10.10.2.3). Changes to study conduct should be documented as described in 
Appendix Section 10.10.3. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 177 of 181 
11. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-76. doi:10.1093/jnci/85.5.365 
Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy 
in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612-2615. 
Bergmann MA, Goebeler ME, Herold M, et al. Results of a phase I/II study of the German CLL 
Study Group. Haematologica. 2005;90(10):1357-1364. 
Bonfiglio S, Scarfo L, Gaidano G, et al. Half of chronic lymphocytic leukemia patients relapsing 
under ibrutinib carry Btk and Plcg2 mutations: A European Research Initiative On Cll (Eric) 
Real-World Study. European Hematology Association Anuual Meeting 2018 Abstract LB 2601. 
Brandhuber B, Gomez E, Smith S, et al. LOXO-305, a next generation reversible BTK inhibitor, 
for overcoming acquired resistance to irreversible BTK inhibitors. Clin Lymphoma Myeloma 
Leuk. 2018;18: S216. 
Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic 
lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437. doi:10.1056/NEJMoa1509388 
Burger JA. Treatment of Chronic Lymphocytic Leukemia. N Engl J Med. 2020;383:460-473. 
doi:10.1056/NEJMra1908213 
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic 
lymphocytic leukemia. N Engl J Med. 2013;369(1):34-42. 
Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic 
lymphocytic leukemia. N Engl J Med.  2016;374(4): 323-332. 
Chang BY, Francesco M, De Rooij MFM, et al. Egress of CD191CD51 cells into peripheral 
blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell 
lymphoma patients. Blood. 2013;122(14):2412-2424. 
Cheson BD, Brugger W, Damaj G, et al. Optimal use of bendamustine in hematologic disorders: 
treatment recommendations from an International Consensus Panel - An update. Leuk 
Lymphoma. 2016;57(4):766-782. 
Cheson BD, Byrd JC, Rai KR et al. Novel targeted agents and the need to refine clinical end 
points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30(23):2820-2822. 
Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition overrides 
a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle 
cell lymphoma. Cancer Discov. 2014;4(9):1022-1035. 
Clinical Trial Facilitation Group (Heads of Medicines Agencies). Recommendations related to 
contraception and pregnancy testing in clinical trials. 2020; 1.1 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 178 of 181 
Cuneo A, Follows G, Rigolin GM, et al. Efficacy of bendamustine and rituximab as first salvage 
treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, 
ERIC and UK CLL FORUM study. Haematologica. 2018;103(7):1209-1217. 
Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical 
Practice Guidelines. Ann Oncol. 2015;26(suppl 5):78-84.  
Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in 
relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446–2455. doi:0.1182/blood-2018-05-
850461 
Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and 
coexisting conditions. N Engl J Med. 2019;380(23): 2225-2236. 
Fischer, K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with 
relapsed and/or refractory chronic lymphocytic leukemia: A multicenter phase II trial of the 
German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;10;29(26):3559-
3566. 
Fischer K, Stilgenbauer S, Schweighofer CD, et al. Bendamustine in combination with rituximab 
(BR) for patients with relapsed chronic lymphocytic leukemia (CLL): A Multicentre Phase II 
Trial of the German CLL Study Group (GCLLSG). Blood. 2008;112(11):330. 
doi:10.1182/blood.V112.11.330.330 
Fraser G, Cramer P, Demirkan F, et al. Updated results from the phase 3 HELIOS study of 
ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small 
lymphocytic lymphoma. Leukemia. 2019;33:969-980. doi:10.1038/s41375-018-0276-9 
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic 
lymphocytic leukemia. N Engl J Med. 2014;370:997-1007. 
Hallek, M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for 
treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25): 
2745-2760. 
Hendriks RW, Bredius RG, Pike-Overzet K, Staal FJ. Biology and novel treatment options for 
XLA, the most common monogenetic immunodeficiency in man. Expert Opin Ther Targets. 
2011;15(8):1003-1021. 
Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in 
patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165-3173. 
doi:10.1182/blood.2021011568. 
Herman SE, Gordon AL, Hertlein A, et al. Bruton tyrosine kinase represents a promising 
therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by 
PCI-32765. Blood. 2011;117(23)6287-6296. 
Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic 
lymphocytic leukemia: The CLARITY study. J Clin Oncol. 2019;37(30);2722-2729. 
Howlader N, Noone AM, Krapcho M, at al. SEER Cancer Statistics Review, 1975-2017, 
National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/csr/1975_2017/, based on 
November 2019 SEER data submission, posted to the SEER website, April 2020. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 179 of 181 
Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia 
after discontinuing ibrutinib. Blood. 2015;125:2062-2067. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L compared 
to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res. 
2013;22(7):1717-1727. 
Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated 
platelet aggregation. Leukemia. 2015;29(4): 783-787. 
Kater AP, Hillmen P, Eichhorst B, et al. First prospective data on impact of minimal residual 
disease on long-term clinical outcomes after venetoclax plus rituximab versus bendamustine plus 
rituximab: Phase III MURANO Study. Presented at: ASH Annual Meeting and Exposition; 
December 4-8, 2018; San Diego, California. Abstract 695. 
Kil LP, de Bruijn MJ, van Hulst JA, Langerak AW, Yuvaraj S, and Hendriks RW. Bruton's 
tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic 
lymphocytic leukemia. Am J Blood Res. 2013;3(1):71-83. 
Lehman CD, Lamb LR, D’Alessandro HA. Mitigating the impact of coronavirus disease 
(COVID-19) vaccinations on patients undergoing breast imaging examinations: A pragmatic 
approach. Am J Roentgenol. 2021; 217:1–3. doi.org/10.2214/AJR.21.25688 
Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies 
(BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi: 
10.1016/S0140-6736(21)00224-5 
Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax 
in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 
2017;28(5):1050-1056. 
Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase 
inhibitor therapy: a real world experience. Blood. 2016;128:2199-2205. 
Mato A, Sail K, Yazdy MS, et al. Treatment sequences and outcomes of patients with CLL 
treated with venetoclax and other novel agents post introduction of novel therapies. Presented at: 
61st American Society of Hematology (ASH) Annual Meeting and Exposition 2019; Abstract 
1756. 
Mato AR, Schuster SJ, Lamanna N, et al. A phase 2 study to assess the safety and efficacy of 
umbralisib (TGR-1202) in patients with chronic lymphocytic leukemia (CLL) who are intolerant 
to prior BTK or PI3K Delta inhibitor therapy. European Hematology Association Annual 
Meeting 2018;Abstract S808. 
McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk 
of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 
2014;124(25):3829-3830. 
Patton DT, Garden OA, Pearce WP, et al. Cutting edge: The phosphoinositide 3-kinase p110δ is 
critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol. 
2006;177(10):6598-6602. 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 180 of 181 
Pound HB, Ho VQ, Bello CM, et al. Bendamustine and rituximab for the treatment of chronic 
lymphocytic leukemia: The Moffitt Cancer Center Experience. Blood. 2011;118(21):4620. 
Rawlings DJ, Saffran DC, Tsukada S, et al. Mutation of unique region of Bruton's tyrosine 
kinase in immunodeficient XID mice. Science. 1993;261(5119): 358-361. 
Rituxan® (rituximab), United States Prescribing Information, Biogen Idec Inc. and Genentech 
Inc. 2010, for injection for intravenous use: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf 
Biosimilar to Rituxan® (rituximab): TRUXIMA® (rituximab-abbs), United States Prescribing 
Information, Teva Pharmaceuticals USA, Inc, 2018; injection, for intravenous use: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761088s000lbl.pdf 
Biosimilar to Rituxan® (rituximab): RUXIENCE™ (rituximab-pvvr), United States Prescribing 
Information, Pfizer Biosimilars, 2019; injection, for intravenous use: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761103s000lbl.pdf 
Biosimilar to Rituxan® (rituximab): RIABNI™ (rituximab-arrx), United States Prescribing 
Information, Amgen, Inc., 2020; injection, for intravenous use: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761140s000lbl.pdf 
Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by 
morphologic subtype: results of the HAEMACARE Project. Blood. 2010;116(19):3724-34. 
Seymour JF, Kipps TJ, Eichhorst B. Venetoclax–rituximab in relapsed or refractory chronic 
lymphocytic leukemia. N Engl J Med. 2018;378:1107-1120. 
Schenkel B, Rider A, Macomson B, Hallworth P. Real-world treatment patterns and 
characteristics in patients with chronic lymphocytic leukemia. J Clin Oncol. 2017;35(8):65-65. 
Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–rituximab or chemoimmunotherapy for 
chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. 
Sharman JP; Coutre SE; Furman RR; Final results of a randomized, phase III study of rituximab 
with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic 
lymphocytic leukemia. J Clin Oncol. 2019;37(16)1391-1402. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA. 2020;70(1)7-30. 
https://doi.org/10.3322/caac.21590. 
Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly 
active in patients with relapsed/refractory B-cell malignancies: Initial report of a phase 1 first-in-
human trial. Blood. 2015;126(23):832-883. 
Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE. Colocalization of X-
linked agammaglobulinemia and X-linked immunodeficiency genes. Science. 1993;261(5119): 
355-358. 
Treanda® (bendamustine), United States Prescribing Information, Cephalon Inc. 2008, for 
(bendamustine hydrochloride) for injection, for intravenous infusion: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022303lbl.pdf 

Loxo Oncology, Inc. 
Clinical Protocol LOXO-BTK-20020 (J2N-OX-JZNN) 
Pirtobrutinib (LOXO-305) 
 
14 June 2024 
 
Version 6.2 
Confidential & Proprietary 
Page 181 of 181 
Tu W, Gierada DS, Joe BN. COVID-19 vaccination-related lymphadenopathy: What to be aware 
of. Radiology: Imaging Cancer. 2021;3(3). doi.org/10.1148/rycan.2021210038. 
Turtle CJ, Hay KA, Hanafi L-A, et al. Durable molecular remissions in chronic lymphocytic 
leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure of 
ibrutinib. J Clin Oncol. 2017;35(26):3010-3020. 
Vetrie DI, Vorechovsky P, Sideras J, et al. The gene involved in X-linked agammaglobulinaemia 
is a member of the src family of protein-tyrosine kinases. Nature. 1993;361(6409):226-233. 
Watson L, Wyld P, Catovsky D. Disease burden of chronic lymphocytic leukaemia within the 
european union. Eur J Haematol. 2008;81(4):253-258.  
WHO: 2014 Review of Cancer Medicines on the World Health Organization [WHO] List of 
Essential Medicines. 
https://www.who.int/selection_medicines/committees/expert/20/applications/CLL.pdf 
Wierda WG, Byrd JC, Abramson JS, et al. Chronic lymphocytic leukemia/small lymphocytic 
lymphoma, Version 4, NCCN Clinical Practice Guidelines in Oncology. JNCCN 
2020;18(2):185-217. 
Woyach JA, Ruppert AS, Guinn D, et al. BTK(C481S-mediated resistance to ibrutinib in chronic 
lymphocytic leukemia. J Clin Oncol. 2017; 35(13): 1437-1443. 
Woyach, JA, Ruppert AS, Heerema D, Zhao W, Booth J, Ding AM, et al. Ibrutinib regimens 
versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 
2018;379(26):2517-2528. 
Woyach JA, Huang Y, Rogers K., et al. Resistance to acalabrutinib in CLL is mediated primarily 
by BTK mutations. Blood. 2019;134(Supplement_1):504. 
Xu L, Tsakmaklis N, Yang G, et al. Acquired mutations associated with ibrutinib resistance in 
Waldenstrom macroglobulinemia. Blood. 2017;129(18): 2519-2525. 
Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of 
lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström 
macroglobulinemia. Blood. 2013;122(7): 1222-1232. 
Zydelig® (idelalisib), United States Prescribing Information, Gilead Sciences Inc. Approved 
2014, Revised 2020, Revised 2022, for (idelalisib) tablets, for oral use: https://www.gilead.com/-
/media/files/pdfs/medicines/oncology/zydelig/zydelig_pi.pdf. 
 

Signature Page for LOXO-BTK-20020-protocol-amendment-v6.2
Signature Page for LOXO-BTK-20020-protocol-amendment-v6.2
Approval Task
14-Jun-2024 13:34:05 GMT+0000
Approval Task
14-Jun-2024 16:56:07 GMT+0000
Approval Task
17-Jun-2024 01:24:14 GMT+0000
PPD
PPD
PPD