Clinical trial NCT05405309
Conditions: Chronic Lymphocytic Leukemia
Sponsor: University of Utah
Start date: 2022-09-23; Completion date: 2025-01-10
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an open-label, multicenter, phase Ib/II study of the combination of RP-3500 and olaparib in Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) patients with DDR deficiencies.

Detailed description:
The Phase Ib part of the trial will seek to assess the Maximum Tolerated Dose (MTD) of camonsertib (RP-3500) in combination with olaparib. Given the potential overlapping toxicities of RP-3500 and olaparib, a keyboard phase I design, a novel Bayesian method that typically underestimates the MTD,61 will be employed. The target toxicity is 30% with an equivalence interval between 25-33% of patients. With an anticipated 3 dose levels (DL) and an option for a DL-1, up to 18 patients may be required to determine the MTD. A maximum of 12 patients will be treated at a DL.

The first 5 patients treated at the previous DL1 (camonsertib 40mg daily and olaparib 100mg two times a day (BID) dosing 3 days per week) determined that this dosing strategy may not be appropriate for R/R CLL patients and reduced dosing may be necessary to increase safety of the combination therapy. Therefore, the newly proposed DLs will seek to enroll an additional 18 patients.

After completion of the phase Ib portion and assignment of the recommended phase 2 dose (RP2D), continuous enrollment of patients may commence into the phase II dose expansion portion. All patients enrolled at the RP2D during the phase Ib dose-escalation portion of the trial can be carried over into the phase II analysis. The maximum number of patients that can be carried over from the dose escalation to the dose-expansion portion is 12.

The phase II dose expansion will consist of two separate cohorts of subjects: an enrichment cohort and a cohort for all other eligible subjects. All subjects enrolled into the enrichment cohort must have a del(11q) and/or ATM mutation. Eight subjects will be enrolled into the enrichment cohort and 16 will be enrolled into the second cohort for a total phase II cohort of 24 patients.

Arms: arm 1: To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 40mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days. arm 2: To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 50mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days. arm 3: To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 80mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days. arm 4: To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 80mg daily and olaparib 150mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days. arm 5: Subjects enrolled into the enrichment cohort must have a del(11q) and/or ATM mutation. arm 6: Cohort will include all other eligible subjects for Dose Expansion. arm 7: To assess the MTD of RP-3500 in combination with olaparib. Before the Aug2023 amendment, patients enrolled at Dose Level 1 received RP-3500 40mg daily and olaparib 100mg BID. Both drugs were given with intermittent dosing of 3 days per week and each cycle was 28 days.
Interventions: intervention 1: RP-3500 intervention 2: Olaparib
Intervention descriptions: intervention 1: RP-3500 is a highly potent and selective Ataxia telangiectasia and Rad3 related inhibitor (ATRi) and has demonstrated significant preclinical activity. intervention 2: Olaparib is an oral poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that inhibits PARP's function by competitively binding to the Nicotinamide adenine dinucleotide (NAD+) binding site, which PARP requires as a cofactor to operate.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 113 
 
A Phase Ib/II Trial of Combination Camonsertib (RP-3500) and 
Olaparib 
in 
DNA 
Damage 
Repair 
Pathway 
Deficient 
Relapsed/Refractory 
Chronic 
Lymphocytic 
Leukemia 
(CORONADO CLL) 
 
Principal Investigator
 
Boyu Hu, MD  
Huntsman Cancer Institute 
2000 Circle of Hope  
Salt Lake City, UT 84112 
Boyu.Hu@hci.utah.edu 
Statistician  
Kenneth M. Boucher, PhD  
Huntsman Cancer Institute  
2000 Circle of Hope Room 1710 
Kenneth.Boucher@hci.utah.edu 
Sponsor  
Huntsman Cancer Institute 
Coordinating Center  
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Compliance@hci.utah.edu  
Investigational Product
 
Camonsertib (RP-3500) 
Commercial  Agent  
Olaparib 
Drug Manufacturer  
Repare Therapeutics 
AstraZeneca 
 
Drug Manufacturer 
Protocol ID  
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 2 of 113 
IND  
160108 
NCT number  
NCT05405309   
HCI IRB number  
141431 
Protocol Version  
Version 4: 28AUG2023 
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 3 of 113 
DOCUMENT HISTORY 
Document 
Date 
Overall Rationale 
Original Protocol  
29APR2022 
Not applicable  
Amendment 1 
06OCT2022 
IB updates, eligibility 
clarifications, SAE reporting 
updates 
Amendment 2 
09MAY2023 
Updated inclusion criteria to 
allow CrCl ≥45 mL/min, 
increased screening 
window to 42 days 
Amendment 3 
28AUG2023 
Updated cycle length and 
dosing Schedule 
 
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 4 of 113 
Table of Contents  
DOCUMENT HISTORY ............................................................................................................. 3 
STATEMENT OF COMPLIANCE .............................................................................................. 8 
PROTOCOL SIGNATURE ......................................................................................................... 9 
ABREVIATIONS  .......................................................................................................................10 
1 
PROTOCOL SUMMARY ...................................................................................................13 
1.1 
Synopsis .....................................................................................................................13 
1.2 
Schema ......................................................................................................................16 
1.3 
Schedule of Events .....................................................................................................17 
1.4 
Long Term Follow-Up .................................................................................................21 
1.5 
Correlative Study Calendar .........................................................................................22 
2 
OBJECTIVES AND ENDPO INTS ......................................................................................23 
2.1 
Primary Objective........................................................................................................23 
2.2 
Secondary Objectives .................................................................................................23 
2.3 
Exploratory Objectives ................................................................................................24 
3 
BACKGROUND AND RATIO NALE ..................................................................................24 
3.1 
Chronic Lymphocytic Leukemia ..................................................................................24 
3.2 
Poorly Prognostic Genetic Aberrations in R/R CLL .....................................................25 
3.3 
Rationale for Combined Inhibition of ATR and PARP ..................................................26 
3.4 
Other CLL Somatic Mutations Affecting the DDR System ...........................................27 
3.5 
Current Treatment Landscape in CLL and Remaining Unmet Needs ..........................28 
3.6 
Olaparib ......................................................................................................................29 
3.7 
RP-3500 .....................................................................................................................29 
3.8 
Combination RP-3500 and Olaparib Shows Preclinical Efficacy and Synergy .............31 
3.9 
Intermittent Dosing of Combination RP-3500 and Olaparib Is Equally Efficacious as 
Continuous Dosing ................................................................................................................32 
3.10 
Combination RP-3500 and Olaparib is More Efficacious at Reduced Doses than RP-
3500 Monotherapy at Higher Doses ......................................................................................33 
3.11 
Rationale for Starting Doses of RP-3500 and Olaparib ...............................................34 
3.12 
Rationale for Allowing Creatinine Clearance (CrCl) Between 45 and 59 mL/min .........35 
4 
STUDY DESIGN ................................................................................................................36 
4.1 
Justification for New Dosing Schema and Dose Escalation .........................................36 
4.2 
Phase Ib Dose Escalation ...........................................................................................37 
4.3 
Phase II Dose Expansion ............................................................................................43 
4.4 
Study Duration and Sample Size ................................................................................43 
4.5 
End of Study ...............................................................................................................43 
4.6 
Duration of Follow Up for PFS and DoR ......................................................................44 
5 
STUDY POPULATION ......................................................................................................44 
5.1 
Inclusion Criteria .........................................................................................................44 
5.2 
Exclusion Criteria ........................................................................................................48 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 5 of 113 
5.3 
Registration.................................................................................................................49 
5.4 
Life Style Considerations ............................................................................................50 
5.5 
Screen Failures ...........................................................................................................50 
5.6 
Strategies for Recruitment ..........................................................................................51 
5.7 
Number of Study Sites ................................................................................................51 
6 
STUDY INTERVENTION ...................................................................................................51 
6.1 
Administration Schedule .............................................................................................51 
6.2 
Olaparib ......................................................................................................................52 
6.3 
Camonsertib (RP-3500) ..............................................................................................53 
6.4 
Dose Interruptions.......................................................................................................53 
6.5 
Dose Reductions ........................................................................................................53 
6.6 
Dose Modifications and Supportive Care Guidelines ...................................................53 
6.7 
Concomitant Medications and Therapies ....................................................................66 
6.8 
Recommended Infectious Prophylaxis ........................................................................66 
6.9 
Duration of Therapy ....................................................................................................67 
6.9.4.1 
Lost to Follow-Up .................................................................................................69 
7 
STUDY ASSESSMENTS ...................................................................................................69 
7.1 
General Assessments .................................................................................................69 
7.2 
Safety Assessments ...................................................................................................71 
7.3 
12-Lead Electrocardiograms .......................................................................................73 
7.4 
Efficacy Assessments .................................................................................................73 
7.5 
Definition of Response and Progression .....................................................................75 
7.6 
Correlative Studies ......................................................................................................79 
7.7 
Remote Visits/Telehealth ............................................................................................80 
8 
ADVERSE EVENTS ..........................................................................................................81 
8.1 
Definitions ...................................................................................................................81 
8.2 
Adverse Event Reporting ............................................................................................82 
8.3 
Special Situations .......................................................................................................86 
8.4 
Data Safety Monitoring Committee .............................................................................87 
9 
STATISTICAL CONSIDER ATIONS ...................................................................................88 
9.1 
Sample size determination ..........................................................................................88 
9.2 
Population for Analyses ..............................................................................................89 
9.3 
Stopping Rules ...........................................................................................................90 
9.4 
Primary Endpoints.......................................................................................................91 
9.5 
Secondary Endpoints ..................................................................................................92 
10 
ETHICAL AND REGULATO RY CONSIDERATIONS ....................................................94 
10.1 
Human Subjects Protection .........................................................................................94 
10.2 
Institutional Review .....................................................................................................94 
10.3 
Investigator Responsibilities ........................................................................................95 
10.4 
Protocol Amendments .................................................................................................95 
10.5 
Protocol Deviations .....................................................................................................95 
10.6 
FDA Reporting ............................................................................................................95 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 6 of 113 
11 
DATA HANDLING  .........................................................................................................95 
11.1 
Recording and Collection of Data ................................................................................95 
11.2 
Data Management ......................................................................................................96 
12 
PUBLICATION PLAN  ....................................................................................................96 
13 
REFERENCES ...............................................................................................................97 
 
List of Figures  
Figure 1.  DNA damage triggers recruitment of DNA damage repair proteins. ...........................26 
Figure 2.  PEO1 and PEO4 are both BRCA2 mutated ovarian cancer cell lines. .......................27 
Figure 3.  Preclinical activity of RP-3500 in Granta-519 mantle cell lymphoma xenograft model
 ..........................................................................................................................................30 
Figure 4. BRCA2-deficient cells are sensitive to RP-3500 and olaparib. ...................................32 
Figure 5. Intermittent dosing of combination RP-3500 and olaparib produced equal efficacy as 
compared to continuous and sequential dosing. ................................................................33 
Figure 6. Efficacy of intermittent sequential versus concomitant RP-3500 plus olaparib in the 
SUM149PT breast cancer xenograft model (BRCA1-deficient), .........................................34 
 
List of Tables  
Table 1. Prevalence of DNA damage repair gene mutations and cytogenetic abnormalities in 
R/R CLL. ............................................................................................................................25 
Table 2. Single-Agent Activity of RP-3500 in ATM and BRCA1/2 Pathway Deficient Human 
Cancer Cell Lines ..............................................................................................................29 
Table 3. PK Clearance of RP-3500 Among Patients with Normal, Mild, and Moderate Renal 
Impairment .........................................................................................................................35 
Table 4. Summary Anemia by Renal Function Categories (CrCL) ............................................35 
Table 5. Summary Neutropenia by Renal Function Categories (CrCL) .....................................36 
Table 6. Summary TESAE by Renal Function Categories (CrCL) .............................................36 
Table 7. Dose levels of RP-3500 and olaparib in phase Ib portion of the trial. ..........................38 
Table 8. Dose escalation rules according to the keyboard phase I design. ...............................38 
Table 10. Modification of Dosing Schedule for Toxicity with Every Week Dosing ......................41 
Table 11.: Dosing Schedule Modifications ................................................................................54 
Table 12. Dose Reduction Levels .............................................................................................54 
Table 13. iwCLL Hematologic Grading .....................................................................................55 
Table 14. Management and dose modification guidelines for hematologic toxicities encountered 
with combination camonsertib (RP-3500) and olaparib. .....................................................56 
Table 15. Management and dose modification guidelines for non-hematologic toxicities 
encountered with combination RP-3500 and olaparib. .......................................................61 
Table 16. Recommended infection prophylaxis medications. ....................................................67 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 7 of 113 
Table 17: Laboratory Assessments ..........................................................................................72 
Table 18. Response definitions and criteria. .............................................................................75 
Table 19: Severity assessment .................................................................................................83 
Table 20:  Lower Bound of a One-sided 95% Confidence Interval for ORR with N = 24 Patients
 ..........................................................................................................................................88 
Table 21: Operating Characteristics of Stopping Rule from toxbdry (N = 34) ............................90 
Table 22: Operating Characteristics of Stopping Rule Under Scenario (N = 34) .......................90 
Table 23: Duration of Response Censoring Criteria ..................................................................92 
Table 24: PFS Censoring Criteria .............................................................................................93 
 
List of Appendices  
Appendix 1: ECOG Performance Status61 ............................................................................. 101 
Appendix 2: Rai and Binet Staging System ........................................................................... 102 
Appendix 3: Subject Dosing Diary ......................................................................................... 103 
Appendix 4: Examples of Strong CYP3A Inhibitors and Inducers, P-GP Inhibitors and BCRP 
Inhibitors .......................................................................................................................... 112 
 
 
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 8 of 113 
STATEMENT OF COMPLIANCE  
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR). 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor, funding agency and documented approval from the Institutional Review 
Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to 
the consent form will be IRB approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 9 of 113 
PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of 
the federal government. I will promptly submit the protocol to the IRB for review and approval. 
Once the protocol has been approved by the IRB, I understand that any modifications made during 
the study must first be approved by the IRB prior to implementation except when such modification 
is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study treatment, the conduct of the study, and the obligations 
of confidentiality. 
This document is signed electronically through submission and approval by the Principal 
Investigator at Huntsman Cancer Institute in the University of Utah IRB Electronic Research 
Integrity and Compliance Administration (ERICA) system. For this reason, the Principal 
Investigator at Huntsman Cancer Institute will not have a hand-written signature on this signature 
page.  
Instructions to multi-site Principal Investigators at locations other than Huntsman Cancer Institute: 
SIGN and DATE this signature page and PRINT your name. Return the original, completed and 
signed, to the HCI Research Compliance Office. Retain a copy in the regulatory binder.  
 
 
 
____________________________________ 
_______________ 
Signature of Principal 
Investigator  
 
Date 
 
 
 
____________________________________ 
Principal Investigator Name (Print)
 
 
 
 
____________________________________ 
Name of Institution  
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 10 of 113 
ABREVIATIONS  
Abbreviation
 
Definition/Explanation
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BCVA 
Best-corrected distance visual acuity 
BICR 
Blinded Independent Central Review 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CLL 
Chronic lymphocytic leukemia 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CMP 
Comprehensive metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450 
CQ 
Chloroquine 


Protocol: CORONADO 
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Page 11 of 113 
Abbreviation
 
Definition/Explanation
 
DILI 
Drug-Induced Liver Injury 
DoR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
Eg 
Exempli Gratia (for example) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
iwCLL 
International Working Group on Chronic Lymphocytic Leukemia 
LDH 
Lactate dehydrogenase 
MRI 
Magnetic resonance imaging 
NIH 
National Institute of Health 
PD 
Pharmacodynamic(s) 
PDAC 
Pancreatic Ductal Adenocarcinoma  
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 


Protocol: CORONADO 
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Page 12 of 113 
Abbreviation
 
Definition/Explanation
 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SD-OCT 
Spectral-domain ocular coherence tomography 
T1/2 
Terminal elimination half-life 
TdP 
Torsades de Pointes 
Tmax 
Time of maximum observed concentration 
ULN 
The upper limit of normal 
VF 
Visual field 
WBC 
White blood cell 
  
 


Protocol: CORONADO 
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Page 13 of 113 
1 
PROTOCOL SUMMARY 
1.1 
Synopsis  
Title:  
Phase Ib/II Trial of Combination RP-3500 and Olaparib in DNA 
Damage Repair Pathway Deficient Relapsed/Refractory Chronic 
Lymphocytic Leukemia (CORONADO CLL) 
Protocol Short Title  
CORONADO CLL 
Study Description:  
Open label, multi-center clinical trial to determine the safety and 
efficacy of combination camonsertib (RP-3500) and olaparib in DNA 
damage repair pathway deficient relapsed/refractory chronic 
lymphocytic leukemia. 
Phase:  
Ib/II 
Objectives:  
 
Primary Objective:   
 
Phase Ib: To assess the maximum tolerated dose (MTD) and 
determine the recommended phase 2 dose (RP2D) of 
combination RP-3500 and olaparib in subjects with 
relapsed/refractory chronic lymphocytic leukemia with DNA 
damage repair deficiencies. 
 
Phase II: To assess the overall response rate (ORR) of 
combination RP-3500 and olaparib in subjects with 
relapsed/refractory chronic lymphocytic leukemia with DNA 
damage repair deficiencies. 
Secondary Objectives:  
 
To assess the safety and tolerability of RP-3500 and olaparib 
in the study population. 
 
To assess progression-free survival (PFS) in the study 
population 
 
To assess overall survival (OS) in the study population 
 
To assess the duration of response (DoR) of the study 
population 
Endpoints:  
Primary Endpoint:   
 
Phase Ib: The rate of dose-limiting toxicities (DLTs) during the 
DLT evaluation period. 
 
Phase II: Overall response rate (ORR) will be defined by the 
proportion of subjects achieving any confirmed partial (PR) 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 14 of 113 
and complete remission (CR) as assessed by 2018 
International Working Group on Chronic Lymphocytic 
Leukemia (iwCLL) response criteria. 
Secondary Endpoints:
 
 
The frequency of adverse events and serious adverse events 
characterized by type, severity (as defined by NIH CTCAE 
v5.0), seriousness, duration, and relationship to study 
treatment. 
 
PFS as defined as the time from study drug initiation to the 
time documented disease progression (as assessed by 2018 
iwCLL criteria) or death from any cause. 
 
OS as defined as the time from registration until death from 
any cause. 
 
DoR as defined as the interval of time from the date of initial 
documented response (PR or better as per 2018 iwCLL criteria 
for response) to the time of progression from the best 
response, the start of a new therapy, or death from any cause. 
Study Population:  
Key Inclusion Criteria:
 
1. Diagnosis of CLL according to the NCI/IWCLL criteria. 
2. Repeat testing of somatic mutations and FISH analysis must 
be performed after progression is noted from most recent line 
of therapy and within 6 months of screening.  Primary CLL 
cells must harbor at least one of these abnormalities:  
 
Somatic gene mutation testing shows mutation(s) in 
TP53, ATM, SF3B1, XPO1 and/or POT1, 
 
Cytogenetic FISH analysis shows deletion 17p13 
and/or deletion 11q22.3, 
3. Relapsed or refractory after at least 2 prior lines of therapy, 
and in the opinion of the treating Investigator are either not 
eligible for other approved therapies or no approved 
therapies are expected to have sustained therapeutic benefit. 
4. Patients in need of treatment as per iwCLL criteria. 
 
Patients on BTK, PI3K or BCL2 inhibitors may enroll 
without meeting iwCLL criteria for treatment as long 
as there is clinical evidence of progression (i.e. 
increasing lymphocytosis, worsening 
anemia/thrombocytopenia attributable to CLL disease 
progression, increasing lymphadenopathy, or 
worsening patient symptoms) and require change in 
treatment at the discretion of the treating provider. 
5. Absolute neutrophil count ≥1000/µL and platelet count 
≥50K/µL (unless documented CLL bone marrow 
involvement). 
6. ECOG performance status between 0-2 
7. Patients must be able to receive xanthine oxidase inhibitor 
and/or rasburicase for tumor lysis syndrome prophylaxis. 


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Page 15 of 113 
Key Exclusion Criteria:
 
1. Patients who are currently receiving any other investigational 
drug. 
2. Prior ATR inhibitor use, but prior PARP inhibitor use for any 
reason is allowed on study. 
3. Evidence of active Richter’s Transformation 
4. Disease states requiring steroids (e.g. adrenal insufficiency, 
autoimmune conditions) are allowed as long as the steroid 
dose is ≤10mg of prednisone or equivalent dose of another 
steroid. Steroids premedications to prevent iodine contrast 
allergy for CT scans are allowed. 
5. Patients who have undergone autologous stem cell 
transplant ≤4 weeks or allogeneic stem cell transplant ≤12 
weeks prior to cycle 1 day 1 or have active graft-versus-host 
disease are excluded. 
6. Patients with active known central nervous system (CNS) 
involvement of CLL. Patients with a history of CNS CLL now 
in remission are eligible for the trial. 
7. Patients with conditions significantly affect gastrointestinal 
function. 
Study Intervention:  
Camonsertib (RP-3500) PO 
Olaparib PO 
Study Duration:  
36 months 
Participant Duration:
 
13 months 


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1.2 
Schema  
 
 
 
RP-3500 
Olaparib  
Dose Level -1# 
40mg daily 
100mg BID 
Dose Level 1* 
50mg daily 
100mg BID 
Dose Level 2* 
80mg daily 
100mg BID 
Dose Level 3* 
80mg daily 
150mg BID 
o Relapsed/refractory CLL after 
2 prior lines of therapy and 
requiring treatment. 
o CLL cells with  at least one of 
the following abnormalities: 
o Somatic mutation(s) in 
TP53, ATM, SF3B1, XPO1 
or POT1 
o Cytogenetic FISH analysis 
shows deletion 17p13 
and/or deletion 11q23 
Phase Ib Dose Escalation  
N=18-23 
 
*Both drugs are given with intermittent dosing 
of 2 days per week.  
Phase II Dose Expansion  
N=24 
Patients enrolled at the RP2D  
from the phase Ib portion will 
also be included in the phase 
II analysis. At least 8 patients 
with deletion 11q23 and/or 
ATM mutation will be included. 


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1.3 
Schedule of Events  
Protocol Activities
 
Screening 1 
On-Treatment Period: One Cycle = 2 1 days  
Post Treatment Period  
Cycle 1  
Cycle 2  
Cycle s 3 & 4 
Cycle 5-18 
EOT2 
Follow -
Up3 
Day of Cycle 
(Visit Window) 
 
1 
2 
3 
8 
(± 1 day) 
15 
(±1 day) 
  
1 
(± 2 days) 
8 
(± 2 days) 
1 
(± 3 days) 
  
1 
(± 7 days) 
(+28 days) 
(+14 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History4 
X 
X 
 
 
 
 
 
 
 
 
 
 
Cancer History5 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Registration6 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments
 
 
 
 
 
Vital Signs7 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Height/ Weight 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Physical Exam 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG8 
X 
X 
 
X  
 
 
 
 
 
 
 
Adverse event collection 
 
Continuous 
Concomitant medications 
X 
Continuous 
 
Laboratory Studies  
 
 
 
 
Hematology9 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Chemistry10 
X 
X 
X 
X X 
X 
 
X 
X 
X 
X 
X 
X 
TLS Labs11 
X 
X 
X 
X X 
X 
 
X 
 
 
 
 
 
24 Hour Urine12 
(X) 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test13 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV and Hepatitis 
Serologies14 
X 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Activities
 
Screening 1 
On-Treatment Period: One Cycle = 2 1 days  
Post Treatment Period  
Cycle 1  
Cycle 2  
Cycle s 3 & 4 
Cycle 5-18 
EOT2 
Follow -
Up3 
Day of Cycle 
(Visit Window) 
 
1 
2 
3 
8 
(± 1 day) 
15 
(±1 day) 
  
1 
(± 2 days) 
8 
(± 2 days) 
1 
(± 3 days) 
  
1 
(± 7 days) 
(+28 days) 
(+14 days) 
IGHV Mutational Status15 
X 
 
 
 
 
 
 
 
 
 
 
 
CLL FISH Analysis16 
X 
 
 
 
 
 
 
 
 
 
 
 
Somatic mutation testing17 
X 
 
 
 
 
 
 
 
 
 
 
 
PB CLL MRD by Flow 
Cytometry18 
 
 
 
 
 
 
 
 
 
X18 
X 
 
BMA CLL MRD by Flow 
Cytometry19 
 
X19 
X19 
 
Disease Assessments  
 
 
 
 
CT Scans 
X 
 
 
 
 
 
 
 
 
X20 
X 
 
Peripheral blood 
immunophenotyping 
X 
 
 
 
 
 
 
 
 
ACI21 
X 
 
Bone marrow biopsy and 
aspirate 
X22 
 
 
 
 
 
 
 
 
(X)23,24 
X24 
 
Correlative Studies  
 
 
 
 
Measurement of DNA 
damage and apoptosis25 
 
X 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
Pharmacokinetics26 
 
X 
X 
 
X 
X 
 
 
 
X26 
 
 
PB CLL MRD by NGS27,28 
(X) 
 
 
 
 
 
 
 
 
X 
X 
 
BM CLL MRD by NGS28 
(X) 
X 
X 
 
Treatment Compliance  
 
 
 
 
Dispense olaparib 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Dispense camonsertib (RP-
3500) 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Xanthine Oxidase Inhibitor 
 
X29 
 
 
 
 
 
 
Dosing diary 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
 


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1 Screening procedures must be completed ≤ 42 days prior to C1D1 unless noted otherwise. 
2 The end of treatment visit should occur when the patient discontinues treatment for any reason. This may be due but not limited to unacceptable 
toxicity from the combination therapy, patient/treating physician preference, progressive disease or completion of 18 cycles of combination therapy 
(whichever comes first). If this visit overlaps with a regularly scheduled visit, only the procedures listed in the calendar for the EOT visit will be 
performed. All end of treatment procedures should be completed ≤ 28 days after discontinuation of treatment.  
3 A follow-up visit will occur 28 (+14) days post the last dose of study treatment. The focused history and physical should discuss residual/lingering 
adverse events experienced by the subject during treatment.. The visit can be performed remotely should the Investigator or subject desire. For 
remote visits, vital signs, height/weight, and laboratory examinations are not required. 
4 Initial medical history at time of screening should include: baseline symptoms; a detailed history of prior cancer therapies including start and stop 
dates, disease progression during or after therapy, as well as discontinuations due to intolerability or any other serious illness; family and social 
history;. 
5 History of the patient’s CLL course will be collected at the screening visit with special attention to prior treatment regimens (duration of therapy, 
best response on therapy, date of discontinuation, toxicities encountered on treatment and reason for discontinuation) and sequence. 
6 To register eligible subjects on study, complete a Clinical Trials Office Subject Registration Form  and submit to CTORegistrations@hci.utah.edu. 
7 Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, pulse oximetry, and body temperature.  
8 ECGs will be performed in triplicate at each time-point; ECG recordings should be completed approximately one minute apart. Patient must rest 
in supine position for at least 5 minutes prior to ECG recording. ECGs should be recorded prior to any blood draw required at the same time-point. 
9 Hematology includes CBC with differential and platelets. 
10 Chemistry includes a Complete Metabolic Panel (Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total 
Bilirubin, Calcium, Carbon Dioxide, Creatinine, Chloride, Glucose, Total Potassium, Protein, Sodium, and Urea Nitrogen).  
11 Tumor lysis syndrome (TLS) labs: lactate dehydrogenase, phosphorus, and uric acid 
12 Optional and can be performed to calculate creatinine clearance instead of the estimated creatinine clearance through Cockroft-Gault equation. 
13 Pregnancy test (serum or urine) must be obtained at screening ≤ 3 days prior to C1D1 for all women of childbearing potential and as clinically 
indicated while on treatment. 
14 Must be conducted within 6 months of registration. 
15 If the subject has had successful testing in the past, this will be accepted and repeat IGHV mutational status will not be required. 
16 Should be performed after progression is noted from most recent line of therapy and within 6 months of screening and should include deletion 
13q14, trisomy 12, deletion 11q22.3, deletion 17p13. 
 
                                               


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17 Should be performed after progression is noted from most recent line of therapy and within 6 months of screening. At a minimum, the following 
somatic mutations must be tested: TP53, ATM, SF3B1, POT1 and XPO1. While not required, the following genes are strongly encouraged to be 
tested as well: NOTCH1, BIRC3, BRAF, KRAS, DDX3X, MYD88 and CXCR4.  
18 CLL MRD testing by flow cytometry should be performed on peripheral blood on C5D1, C9D1 and EOT.  
19 BM MRD testing by flow cytometry through a local lab should be performed on any BM aspirate obtained after screening. An additional aspirate 
sample should be collected and processed for correlative studies.   
20 At C5D1 (±7 days): CT scans of the neck, chest, abdomen and pelvis should be performed with contrast agents unless contraindicated for 
medical reasons. Should this CT show that the patient has achieved an iwCLL 2018 defined complete remission and absolute lymphocyte count is 
<4000, then a bone marrow biopsy should be performed at this time to confirm the complete remission. At any other study time point beyond 
C5D1 (excluding end of treatment): If patient achieves hematologic recovery or the treating physician suspects the patient has achieved a 
complete remission per the 2018 iwCLL criteria,  then a peripheral blood immunophenotype should be ordered. Should this show no evidence of 
circulating CLL cells, then a complete remission can be confirmed with CTs of the neck, chest, abdomen and pelvis along with a bone marrow 
biopsy. If CTs and bone marrow biopsy are indicated, studies need to be performed within 28 days. 
21 If subject achieves hematologic recovery or the treating physician suspects the patient has achieved a complete remission as per the 2018 
iwCLL criteria, then a peripheral blood immunophenotype should be ordered. Please refer to reference 20 for sequencing of testing to confirm a 
complete remission. 
22 The bone marrow biopsy  performed at screening  should be after progression is noted from most recent line of therapy and within 6 months of 
screening. If a bone marrow biopsy is not performed at screening, an archival tissue maybe requested at the discretion of the PI. BM CLL MRD by 
NGS should be performed on any BM aspirate obtained after screening.  
23 Should peripheral blood immunophenotying show no evidence of circulating CLL cells, then a complete remission can be confirmed with CTs of 
the neck, chest, abdomen and pelvis and a bone marrow biopsy. Please refer to reference 20 for sequencing of testing to confirm a complete 
remission. 
24 BMBx at screening and EOT are the only ones required on study. If a prior bone marrow biopsy showed the patient to be in a complete 
remission, a repeat bone marrow biopsy is not required unless progression of disease is suspected. 
25 Samples should be collected prior to dosing of the drugs. Samples should be collected on C1D1, C1D8, C1D15, C2D1, C2D8 and at time of 
progression.  
26 Refer to section 1.5.1 for time points 
27 PB CLL MRD by NGS should be performed on peripheral blood on C5D1, C9D1 and EOT as tracking samples.. 
28 The treating physician may choose to collect the identification sample for MRD by NGS on either the PB or BM at screening depending on which 
compartment has CLL cells present. Thus, two samples (one from PB and one from BM) for MRD by NGS at screening are not required. 
29 Xanthine oxidase inhibitor agent must be given at least 72 hours prior to C1D1 and during the first cycle of study therapy. 
 
 


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1.4 
Long Term Follow -Up 
Activities 1 
Year 1 
Year 2-52 
Year 6-102 
Office visit for 
history and 
physical3 
Every 3 months 
(±14 days) 
Every 3-6 months 
(±14 days) 
Every 3-12 months 
(±28 days) 
Labs4 
Every 3 months 
(±14 days) 
Every 3-6 months 
(±14 days) 
Every 3-12 months 
(±28 days) 
 
 
 
 
 
 
1 Long term follow-up is calculated from the last date that the patient took any study drug. 
2 Follow up length in years 2-10 is at the discretion of the treating physician. 
3 An abbreviated history and physical can be performed, but should include signs or symptoms of CLL relapse or disease 
progression. This includes B-symptoms (fevers, drenching night sweats, unintentional weight loss), new palpable lymphadenopathy 
and/or hepatosplenomegaly, new or progressive symptoms from the patient’s last visit. 
4 Hematology includes CBC with differential and platelets. Chemistry includes a Complete Metabolic Panel (Albumin, Alkaline 
Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, Chloride, 
Glucose, Total Potassium, Protein, Sodium, and Urea Nitrogen). 
                                               


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1.5 
Correlative Study Calendar
 
1.5.1 Pharmacokinetic 
 
 
 
 
 
 
 
1 ECGs will be performed in triplicate at each time-point; ECG recordings should be completed approximately one minute apart. 
Patient must rest in supine position for at least 5 minutes prior to ECG recording. ECGs should be recorded prior to any blood draw 
required at the same time-point. 
                                               
Cycle 1 
Day 1 
Day 3 
Day 8 (±1 day) 
Day 15 (±1 day) 
Time of Collection (hours after 
drug dosing) 
Pre 
0.5 
1 
2 
4 
24 
Pre 
Pre 
0.5 
1 
2 
4 
Pre 
0.5 
1 
2 
4 
24 
Time Window for Collection 
(min) 
 
±5 
±10 
±15 
±15 
±120 
 
 
±5 
±10 
±15 
±15 
 
±5 
±10 
±15 
±15 
±120 
PK Blood Draw 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG1 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cycle 5 
Day 1 
Time of Collection (hours after drug dosing) 
Pre 
0.5 
1 
2 
Time Window for Collection (min) 
 
±5 
±10 
±15 
PK Blood Draw 
X 
X 
X 
X 


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2 
OBJECTIVES AND ENDPOINTS  
2.1 
Primary Objective  
2.1.1 Phase Ib: To assess the maximum tolerated dose (MTD) and determine the 
recommended phase 2 dose (RP2D) of combination RP-3500 and olaparib in subjects with 
relapsed/refractory chronic lymphocytic leukemia with DNA damage repair deficiencies. 
Primary endpoint: The rate of dose-limiting toxicities (DLTs) during the DLT evaluation 
period.  
2.1.2 Phase II: To assess the overall response rate (ORR) of combination RP-3500 and 
olaparib in subjects with relapsed/refractory chronic lymphocytic leukemia with DNA damage 
repair deficiencies. 
Primary endpoint: Overall response rate (ORR) will be defined by the proportion of 
subjects achieving any confirmed partial (PR) and complete response (CR) as assessed 
by 2018 International Working Group on Chronic Lymphocytic Leukemia (iwCLL) 
response criteria. 
2.2 
Secondary Objectives  
2.2.1 To assess the safety and tolerability of RP-3500 and olaparib in the study population. 
Secondary Endpoint: The frequency of adverse events (AEs) and serious adverse events 
(SAEs) characterized by type, severity (as defined by the NIH CTCAE, version 5.0), 
seriousness, duration, and relationship to study treatment. 
2.2.2 To assess progression-free survival (PFS)  
Secondary Endpoint: Progression-free survival (PFS) as defined as the time from study 
drug initiation to the time documented disease progression (as assessed by 2018 iwCLL 
criteria) or death from any cause.  
2.2.3 To assess overall survival (OS) in this study population 
Secondary Endpoint: OS as defined as the time from registration until death from any 
cause. 
2.2.4 To assess the duration of response (DoR) of the study population. 
Secondary Endpoint: DoR as defined as the interval of time from the date of initial 
documented response (PR or better as per 2018 iwCLL criteria for response) to the time 
of progression from the best response, the start of a new therapy, or death from any cause. 


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2.3 
Exploratory Objecti ves 
2.3.1 To evaluate protein expression levels of γH2AX, annexin V, cleaved PARP1 and cleaved 
caspase 3 during treatment with combination RP-3500 and olaparib as markers of DNA damage 
and apoptosis. 
Exploratory Endpoint #1: Correlation of protein expression levels to best overall response 
and minimal residual disease status. 
Exploratory Endpoint #2: Trend of protein expression levels at the beginning of therapy as 
compared to at the time of suspected relapse. 
2.3.2 To assess the effects of combination of RP-3500 and olaparib on minimal residual 
disease status. 
Exploratory Endpoint: Proportion of patients achieving undetectable minimal residual 
disease as assessed by either flow cytometry and/or next generation sequencing 
methods. 
2.3.3 To determine the pharmacokinetic properties of combination RP-3500 and olaparib in 
relapsed/refractory chronic lymphocytic leukemia. 
Exploratory Endpoint: Peripheral blood RP-3500 and olaparib concentrations when each 
are given at varying doses. 
2.3.4 To correlate ORR, PFS and OS to DNA damage repair gene alterations  
Exploratory Endpoint: ORR, PFS and OS according to each DNA damage repair gene 
alterations for which the patient was enrolled. 
3 
BACKGROUND AND RATIONALE  
3.1 
Chronic Lymphocytic L
eukemia  
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia with approximately 
21,000 new cases per year1. The disease is still generally considered incurable with an estimated 
3930 deaths in the United States for the year 20191. Recent advances in the characterization of 
the biological drivers of the disease have shifted CLL treatments from chemo-immunotherapy to 
targeted and specific small molecule inhibitors (i.e. ibrutinib and venetoclax). While these targeted 
therapies are effective at controlling relapsed/refractory (R/R) disease, progression and relapse 
are inevitable with many of these patients eventually dying2,3. Therefore, new treatment strategies 
are desperately needed. Over the years, genomic and chromosomal profiling of these R/R CLL 
patients have shown a predominance of somatic mutations and/or cytogenetic abnormalities 
within the DNA damage repair (DDR) pathways4,5. While these intrinsic deficiencies in the CLL’s 
DDR system offer the disease a survival advantage, they can also be exploited for therapeutic 
benefit. 


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3.2 
Poorly Prognostic Genetic Aberrations in 
R/R CLL 
CLL is a clinically heterogeneous disease with 
highly variable outcomes.  Somatic gene mutations 
and 
chromosomal 
abnormalities 
have 
been 
identified as underlying risk factors for resistance to 
therapy and shortened survival in CLL patients1-3.  
Specifically, 
the 
CLL genetic 
landscape is 
represented by a high prevalence of mutations 
affecting DDR genes, including TP53, ATM, 
SF3B1, XPO1 and POT1 (Table 1. Prevalence of 
DNA 
damage 
repair 
gene 
mutations 
and 
cytogenetic abnormalities in R/R CLL.)1-4, which 
conveys resistance to both upfront and salvage 
treatments and portends worse survival outcomes1-
3,5-8.  Compared to newly diagnosed patients, these 
high-risk genetic defects are enriched in R/R 
patients, and result in poor progression-free 
survival (PFS) and overall survival (OS) of 6-9 and 
20-30 months, respectively, when treated with 
chemotherapy or lenalidomide-based therapies1-4. 
Furthermore, chromosomal abnormalities have 
been frequently shown to co-occur with some of 
these gene mutations such as deletion 17p13 
[del(17p)] with TP53 mutation and deletion 11q22.3 
[del(11q)] with ATM and SF3B1 mutations1,3,4,6.  These concurrent chromosomal and genetic 
alterations help to explain the poor prognoses and almost absent responses to chemotherapy in 
CLL patients harboring these cytogenetic abnormalities9,10.  Due to the poor clinical outcomes in 
R/R CLL patients with DDR deficient gene mutations and cytogenetic aberrations, these patients 
remain an area of unmet need. 
3.2.1 DDR and Cell Cycle Checkpoint Mechanisms in Non-Malignant Cells  
Ataxia telangiectasia and Rad3 related (ATR) protein is an essential kinase for cell viability. DNA 
damage at the replication fork is recognized by ATR to ensure mitotic arrest, allowing sufficient 
repair of the damage prior to re-initiation of replication11. Single-strand DNA breakage (SSB) 
repair is led by poly (ADP-ribose) polymerase (PARP) while double-strand DNA breakage (DSB) 
repair is directed by ATM12-14. Crosstalk between DDR and cell cycle checkpoint proteins is 
mediated by TP53 to halt cellular division and if needed, to trigger apoptosis (Figure 1. DNA 
damage triggers recruitment of DNA damage repair proteins.)14. While non-malignant cells utilize 
all of these mechanisms for DDR and cell cycle checkpoints, R/R CLL patients with DDR 
deficiencies are dependent on ATR and PARP for DDR, genomic stability and cell survival (Figure 
1. DNA damage triggers recruitment of DNA damage repair proteins.). 
Table 1. Prevalence of DNA damage 
repair gene mutations and cytogenetic 
abnormalities in R/R CLL. 
Gene Mutation  
Prevalence  
TP53 
15-25% 
ATM 
10-15% 
SF3B1 
10-15% 
XPO1 
~5% 
POT1 
~5% 
Cytogenetic Abnormality
 
Prevalence  
Deletion 17p13 
15-25% 
Deletion 11q22.3 
10-20% 
Total  
50-70%* 
* Patients may harbor mutational and cytogenetic 
co-occurrences such as del(17p) with TP53 
mutation, del(11q) with ATM and SF3B1 mutations, 
which is why the predicted total prevalence of these 
abnormalities is 50-70% 


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Figure 1. DNA damage triggers recruitment of DNA damage repair proteins.  
A) ATR regulates replication fork initiation to maintain genomic integrity. PARP is required for 
single-strand DNA damage repair whereas ATM is required for double-strand repair. If excessive 
DNA damage is present, TP53 is activated to initiate cell cycle arrest and apoptosis. B) Since 
relapsed/refractory CLL patients are deficient in either ATM and/or TP53, genomic integrity and 
DNA damage repair are solely dependent on ATR and PARP. 
 
3.3 
Rationale for Combined Inhibition of ATR and PARP
 
Treatment of cell and murine models of TP53- or ATM-deficient CLL with an ATR inhibitor (ATRi) 
or a PARP inhibitor (PARPi) have shown significant single-agent activity. The use of the PARPi, 
olaparib, increased DNA damage and mitotic catastrophe in ATM-deficient CLL cell lines, which 
led to decreased proliferation and increased cytotoxicity as compared to ATM-proficient cells15. 
Notably, the drug had almost no activity in the ATM-wildtype control cell lines and showed no 
noticeable escalation of DNA damage. Similarly in mice, ATM-deficient CLL mice treated with 
olaparib had a statistically significant decrease in circulating CLL cells and in spleen volume as 
well as prolonged survival when compared to the control mice16. In contrast, the ATM-proficient 
control mice showed no difference in the measured parameters when treated with either vehicle 
or olaparib, suggesting that ATM-deficient CLL is dependent on PARP for survival. Similarly, the 
use of the ATRi, AZD6738, showed significant responses in ATM- and TP53-mutated CLL cell 
lines as compared with wildtype ATM and TP53 CLL cells and healthy donor lymphocytes17. 
However, a small phase I clinical trial using olaparib single agent for the treatment of 9 CLL 
patients showed a modest benefit for ATM-deficient patients with a non-statistically significant 
improvement in overall survival by 103 days as compared to wildtype patients18. This study 
highlights the challenges of PARPi treatment due to the high prevalence of acquired or innate 
resistance to single-agent PARPi. Preclinical data in solid tumors have shown these resistance 
mechanisms to include reversion of DDR mutations to wildtype, promoter demethylation of 
suppressed DDR genes, mitigation of replication stress and mutations in PARP19,20.  


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In order to overcome PARP resistance, 
the addition of ATRi to a PARPi has 
shown both preclinical efficacy and 
synergy. In breast and ovarian cancer 
patients with germline deficiencies of 
DSB 
repair 
proteins, 
such 
as 
BRCA1/BRCA2, treatment with PARPi 
is highly efficacious and improves 
survival in these diseases as compared 
to 
conventional 
chemotherapy21-23.  
These pivotal clinical trials in breast and 
ovarian cancer patients have proven the 
concept of synthetic lethality in which 
the loss of function of one component of 
cell survival (i.e. BRCA1/BRCA2) does 
not have significant impact on cancer 
fitness, but the combined deficit of two 
vital and inter-dependent elements (i.e. 
PARP and BRCA1/BRCA2) leads to 
tumor death24. Combination strategies to incite improved synthetic lethality have been explored 
in BRCA1/BRCA2 mutated ovarian cell lines in which the combination of ATRi and olaparib was 
synergistic in producing increased apoptosis and cell death (Figure 2. PEO1 and PEO4 are both 
BRCA2 mutated ovarian cancer cell lines.)25. Furthermore, PARPi resistant BRCA-deficient cell 
lines show an increased reliance on ATR signaling fork stabilization and PARP sensitivity can be 
restored by using a combination ATRi and PARPi strategy26. Therefore, we hypothesize that the 
rational combination of an ATRi in combination with a PARPi would be highly efficacious and 
potentially synergistic in high-risk CLL patients carrying somatic mutations in TP53, ATM, SF3B1, 
XPO1 and POT1 or cytogenetic abnormalities such as del(17p) and del(11q). 
3.4 
Other CLL Somatic Mutations Affecting the DDR S
ystem  
While the use of PARPi in CLL patients with mutations in TP53 and ATM is apparent, its use in 
SF3B1, XPO1 and POT1 mutated patients are also scientifically rational. SF3B1 is a part of the 
mRNA spliceosome and has been shown to co-occur with both del(11q) and ATM 
mutations4,6,27,28. Its effects on the DDR system is due to decreased synthesis of various DDR 
proteins in a manner that is independent of ATM downregulation, leading to increased DNA 
breakage and decreased apoptosis28. Therefore, SF3B1 co-occurrence with del(11q)/ATM gene 
mutation leads to genomic instability by increasing DNA damage and decreasing DDR. In a 
similarly indirect manner, XPO1 transports tumor suppressor proteins out of the nucleus in the 
absence of DNA damage, but its recurrent hotspot mutation at E571 most likely enhances its 
binding to DDR proteins and inappropriately sequesters them in the cytoplasm, rendering them 
ineffective4,29,30. This leads to increased DNA stress and damage with decreased capacity for 
DDR29. Lastly, POT1 is a critical protein for maintaining DNA telomere stability and POT1 loss-of-
function mutations lead to reduced telomere capping, fusion and lengthening, which then 
decreases DNA integrity and increases genomic instability31,32. While mutations in additional DDR 
Figure 2. PEO1 and PEO4 are both BRCA2
mutated ovarian cancer cell lines.  
Treatment with combination PARPi and ATRi 
showed synergy as compared to single agent 
therapy. 


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genes have been implicated in CLL, the ones specifically chosen here have a clinically significant 
frequency of at least 5% in R/R CLL patients4. 
3.5 
Current Treatment Landscape in CLL and Remaining Unmet Needs
 
Recent approvals of targeted therapies such as Bruton’s Tyrosine Kinase inhibitors (BTKi) and 
venetoclax for both the frontline and salvage treatments of CLL have dramatically changed the 
treatment paradigms for the disease33-36.  Specifically, these drugs have become standard for 
high-risk patients with del(17p) and TP53 mutation as prior studies have shown that treatment of 
these patients with chemotherapy leads to almost absent responses and poor survival outcomes1-
3.  Recent real world data collected between 2015-2019 showed that ~45% of previously untreated 
and ~60% of R/R of CLL patients were treated with targeted therapies37. The majority of this data 
was abstracted before the FDA approvals of frontline venetoclax in May/2019 and acalabrutinib 
in November/2019 for the treatment of CLL patients. Therefore, present day use of targeted 
agents for the frontline treatment of CLL patients far exceeds the prior reported 45%. Furthermore, 
multiple clinical trials have investigated the efficacy of combination ibrutinib and venetoclax in the 
frontline (NCT02910583, NCT03701282, NCT03737981) and R/R settings38. Therefore, R/R CLL 
patients with DDR pathway deficiencies who have failed both BTKi and venetoclax have no known 
effective treatments. 
3.5.1 Safety Profile of BTKi and Venetoclax Limit Their Use in Patients with Comorbidities 
Toxicities associated with BTKi and venetoclax treatment limit its use. In a 5-year follow up of 
ibrutinib-treated patients showed only 55% of treatment-naïve patients remained on drug due to 
progression, intolerable side effects or patient preference while 72% of R/R patients had 
discontinued5. In the MURANO trial investigating rituximab/venetoclax for R/R CLL patients, 33% 
of patients discontinued treatment prior to finishing the 2-years of therapy with 15% of patients 
coming off study due to adverse events34,36. While overall response rates are high with ibrutinib, 
complete responses (CR) in R/R CLL patients are only 10%5. Since CLL is a disease of the elderly 
with a median age at diagnosis of 70 years old, many patients with CLL have concurrent 
comorbidities. For example, patients with chronic kidney disease and high CLL tumor burden are 
at increased risk for tumor lysis syndrome when treated with venetoclax therapy, making 
venetoclax difficult to administer safely39. BTKi have high rates of cardiac toxicities and 
bleeding5,40,41. The use of BTKi in CLL patients with cardiac comorbidities or who require 
anticoagulation or anti-platelet therapies can be difficult and result in sudden cardiac death or 
major bleeding42. Therefore, alternative effective therapies are required for these patients, 
especially if they concurrently harbor high-risk CLL genetic aberrations. 
3.5.2 Inclusion of High-Risk CLL Patients With No Known Effective or Safe Treatments 
Altogether, the high-risk CLL patient who has discontinued chemotherapy, BTKi and/or 
venetoclax due to either disease progression or intolerable side effects will remain a challenge to 
treat in the future as there are currently no effective therapies.   
Combination RP-3500 and olaparib treatment can fulfill these unmet needs within the R/R CLL 
treatment landscape: 1) currently approved targeted therapies for CLL treatment are heavily being 
used in upfront treatment as most clinicians are no longer treating with chemo-immunotherapy. 
Multiple current and former clinical trials are investigating combination BTKi and venetoclax in 


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frontline and R/R settings, thus exhausting these treatments earlier in the CLL patient’s disease 
course. 2) BTKi are not as effective in treating CLL patients with high-risk cytogenetic 
abnormalities such as del(17p) and del(11q). BTKi treatments rarely induce CRs and uMRD 
status and therefore, need to be given life-long, which adds to both patient cost and 
dissatisfaction. 3) Venetoclax-based treatments are also less effective for CLL patients with high-
risk cytogenetic abnormalities. While venetoclax-based treatments are for a fixed duration, 
efficacy of venetoclax re-challenge due to progressive disease after treatment discontinuation is 
unknown, which is especially relevant when venetoclax is being increasingly used in the frontline 
setting. 4) Toxicities associated with BTKi and venetoclax leading to treatment discontinuation 
can be high especially in an elderly CLL patient population with comorbidities, making either class 
of drugs not safe to use. Due to these unmet needs in the CLL treatment paradigm, combination 
RP-3500 and olaparib treatment can be a highly effective, fixed-duration treatment for R/R CLL 
patients with high-risk genetic aberrations related to DNA damage repair (i.e. del(17p), del(11q); 
gene mutations in TP53, ATM, SF3B1, XPO1 and POT1). 
3.6 
Olaparib  
Olaparib is an oral PARPi that inhibits PARP’s function by competitively binding to the NAD+ 
binding site, which PARP requires as a cofactor to operate.  This leads to decreased recruitment 
of PARP’s downstream substrates and also traps PARP onto the DNA so that other components 
of the SSB complex cannot bind to the damaged site43. Olaparib has multiple FDA approved 
indications in DDR-deficient solid tumors including ovarian, breast, pancreatic and prostate 
cancers21,44-49. Compared to other PARPi, olaparib has moderate potency, leading to a more 
favorable cytopenia-related toxicity profile with grades 3-4 anemia, neutropenia and 
thrombocytopenia occurring in 7-20%, 3-11%, and 1-4% of patients treated with continuous 
300mg or 400mg BID dosing, respectively21,44-49. 
3.7 
RP-3500 
RP-3500 is a highly potent and selective ATRi and has demonstrated significant preclinical 
activity. Pharmacokinetic (PK) and pharmacodynamic marker analysis from tumor xenografts 
demonstrates target engagement and a dose-responsive increase in double-strand DNA breaks 
leading to tumor cell death in vivo. RP-3500 is a potent ATR kinase inhibitor with a Ki of 0.022 nM 
determined in a biochemical ATR assay using p53 as a substrate. RP-3500 induced cell death in 
the low nM range in a panel of cancer cell lines with ATM or BRCA1/2 pathway defects in 5-day 
cell-based cytotoxicity assays (Table 2. Single-Agent Activity of RP-3500 in ATM and BRCA1/2 
Pathway Deficient Human Cancer Cell Lines). 
Table 2. Single-Agent Activity of RP-3500 in ATM and BRCA1/2 Pathway Deficient Human 
Cancer Cell Lines 
Cell Line  
Cancer Type  
Genetic Aberration  
IC50 (nM)a  
Lovo 
Colon adenocarcinoma 
MRE11 (Del exon 5) 
29±10 
NCI-H23 
Non-small cell lung adenocarcinoma ATM (Q1919P) 
13±4 
CW-2 
Colon adenocarcinoma 
ATM (A2843V) 
17±5 
Capan-1 
Pancreatic adenocarcinoma 
BRCA2 (6174delT)/- 
57±4 
SUM-149-PT 
Triple-negative breast cancer 
BRCA1 (2288delT)/- 
7±3 


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Granta-519 
Mantle cell lymphoma 
ATM (R2832C) 
8.3±2 
a. IC50 values are the mean ± standard deviation of n≥3 independent experiments. 
RP-3500 is also highly selective for ATR and does not compete an ATP binding pocket probe on 
>300 kinases probed in a cell lysate binding assay at 300 nM. Kinases that bind to RP-3500 at 
higher concentrations represent members of the closely related PIKK family. In biochemical 
assays measuring inhibitory activity of the related PIKK family of kinases, RP-3500 exhibits at 
least a 120-fold selectivity over mTOR, ATM, DNA-PK, and PI3Ka. Furthermore, RP-3500 is >31-
fold selective for ATR kinase over mTOR and >2000-fold over ATM, DNA-PK, and PI3Ka in cell-
based kinase assays. 
3.7.1 Intermittent Dosing Rationale  
Significant preclinical activity of RP-3500 was demonstrated in Granta-519 mantle cell lymphoma 
xenograft model in which intermittent dosing schedule of the drug at 30 mg/kg QD 3 days per 
week showed the best efficacy and least toxicity (Figure 3 ). 
 
3.7.2 RP-3500 Clinical Pharmacokinetics 
In an ongoing Phase 1 dose escalation study of RP-3500 (NCT04497114) in patients with 
advanced cancer, the PK has been evaluated at doses from 5 mg to 20 mg QD. The available 
Figure 3. Preclinical activity of RP-3500 in Granta-519 mantle cell lymphoma 
xenograft model 
 A) Tumor xenograft volume and (B) Hematocrit from female NOD-SCID mice bearing 
Granta-519 tumors treated PO with RP-3500 at MTD on different weekly dosing 
schedules as indicated. RP-3500 was administered QD in 0.5% MC/0.02% SLS 
vehicle in sequence followed by a recovery phase for the remainder of the week.  
Results are expressed as mean ± SEM, N=9/group. Tumor volumes were measured 
by electronic caliper; volume = 0.52*L*W2.  Blood parameters including hematocrit 
were measured on day 14 at termination and are expressed as the mean ± 
SEM.   Blood samples from some mice were not available.  Red dashed lines indicate 
reference hematocrit range from female age and strain matched mice (Charles 
River). Statistical significance relative to vehicle control was established by Student’s 
T-test (GraphPad Prism v8); ns; not significant; *p <0.05; **p <0.01; *** p <0.001; **** 
p<0.0001.  


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bioanalytical data as of 11 November 2021 were analyzed in a draft noncompartmental analysis 
(NCA) using nominal sampling times to determine the PK. The results of the draft analysis 
indicated a half-life ranging from 2.7 to 23.0 hours with a mean half-life across all QD dose groups 
of 6.4 hours. Across all cohorts, the Tmax is in the range of 0.5 to 4 hours in the fasted state. 
Additionally, both Cmax and area under the plasma concentration-time curve from time 0 to time 
of last quantifiable concentration (AUC0-t) have increased in roughly a dose-linear fashion. The 
mean ± standard error (SE) Cmax at the therapeutic dose levels of 120 mg and 160 mg QD are 
5.17 ± 0.25 μg/mL and 7.36 ± 0.25 μg/mL, respectively. The mean AUC0-t ± SE at these dose 
levels was 34.2 ± 15.8 μg•hr/mL and 47.8 ± 20.7 μg•hr/mL, respectively. 
3.7.3 RP-3500 Drug-Drug Interactions 
Definitive in vitro drug-drug interaction studies have been conducted as per the recommendations 
of the Food and Drug Administration (FDA) Guidance for Industry (FDA, 2020). In definitive in 
vitro studies, RP-3500 did not appreciably inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19, 
CYP2D6, CYP3A4/5 [testosterone as substrate], or CYP3A4/5 [midazolam as substrate] with a 
half maximal inhibitory concentration [IC50] >100 μM), and was found to be a weak direct inhibitor 
of CYP2C8 (IC50 = 44 μM) in these same studies. RP-3500 was not a preincubation or time-
dependent inhibitor of all CYP isoforms evaluated. Incubations of human hepatocytes with RP-
3500 showed only minor increases in CYP2B6 and CYP3A4 messenger RNA that did not exceed 
more than 20% of the associated positive control values. Experiments using cell systems have 
shown that RP-3500 is not an inhibitor of the uptake transporters organic anion transporting 
polypeptide 1B1 (OATP1B1), organic anion transporting polypeptide 1B3 (OAT1B3), organic 
anion transporter 1 (OAT1), organic anion transporter 3 (OAT3), organic cation transporter 1 
(OCT1), or multidrug and toxin extrusion protein 2-K (MATE2-K). RP-3500 is a weak inhibitor of 
multidrug and toxin extrusion protein-1 (MATE-1; 44% inhibition at 5 μM), multidrug resistance 1 
(MDR1; 40% inhibition at 100 μM), and breast cancer resistance protein (BCRP; IC50 = 17.4 μM). 
Together the data suggest that RP-3500 has a low potential to be a perpetrator of drug-drug 
interactions with co-administered transport substrates, however depending on the dose, RP-3500 
may inhibit BCRP in the gastrointestinal tract and increase the absorption of BCRP substrates. 
Additionally, based on the current data, RP-3500 is not expected to be a perpetrator of drug-drug 
interactions at the levels of inhibition, or induction of CYP isoforms. 
The current data from in vitro experiments suggests that that RP-3500 is a substrate of both P-
glycoprotein (P-gp) and BCRP drug transporters, and CYP3A4 and CYP2C8 appear to be the 
major isoforms responsible for the CYP-mediated metabolism of RP-3500 in vitro. Based on the 
currently available data, it is recommended that administration of strong P-gp and BCRP inhibitors 
as well as strong CYP3A inhibitors and/or inducers including food and herbal sources should be 
excluded while on study and at least 14 days prior to initiating treatment with RP-3500 until further 
clinical evaluation is available. 
3.8 
Combination RP -3500 and Ola parib Shows Preclinical Efficacy and Synergy
 
Using an isogenic DLD1 colorectal cancer cell line system, combination RP-3500 and olaparib at 
sub-lethal doses was profoundly cytotoxic to breast cancer type 2 susceptibility protein-knockout 
(BRCA2-KO) cells, while minimally affecting the viability of wild type (WT) cells (after 8 or 6 days 


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of treatment, respectively) (Figure 4A). The combination also showed a strong synergistic effect 
on viability at markedly lower concentrations in BRCA2-KO cells than WT (Figure 4B).  
 
Figure 4. BRCA2-deficient cells are sensitive to RP-3500 and olaparib. 
 
3.9 
Intermittent Dosing of Comb
ination RP -3500 and Olaparib Is  Equally Efficacious as 
Continuous Dosing  
In the same DLD1 BRCA2-KO cell model, reducing the treatment time of combination RP-3500 
and olaparib to 3 days followed by removal of the compounds for 5 days was equally as efficacious 
in killing BRCA2-KO cells as 8 days of continuous treatment (Figure 5A). These findings were 
confirmed using a different cell model of SUM149PT, which are BRCA1-mutated triple negative 
breast cancer cells. Intermittent dosing of the drug combination (3 days on 5 days off) produced 
equal efficacy as compared to continuous 8 day dosing and increased efficacy as compared to 
sequential dosing (i.e. olaparib treatment for 3 days alone followed by RP-3500 treatment for 3 
days alone followed by 2 days off) (Figure 5B). These findings support intermittent dosing of the 
drug combination. 
 
 
 
 


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Figure 5. Intermittent dosing of combination RP-3500 and olaparib produced equal efficacy as 
compared to continuous and sequential dosing. 
A) DLD1 BRCA2-KO and B) SUM149PT (BRCA1-mutated triple negative breast cancer) cell 
models 
 
 
3.10 Combination  RP-3500 and Ola parib  is More Efficacious at Reduced Doses than RP
-
3500 Monotherapy at Higher Doses
 
Dosing strategies for combination RP-3500 and olaparib were explored in SUM149PT xenograft 
mice models. Concomitant administration of RP-3500 with olaparib for 3 days weekly resulted in 
higher efficacy than sequential administration (Figure 6). Furthermore, intermittent administration 
of RP-3500 and olaparib was well tolerated with <5% body weight loss over the course of the 
experiment compared to continuous concomitant dosing schedules (data not shown). The 
olaparib doses selected in this study represent exposure levels of ~11 μM, which is comparable 
to ~40% of the circulating free drug exposure levels of olaparib at steady state in humans taking 
300 mg BID daily. This dose is less than the maximum tolerated dose (MTD) of 400mg BID as 
previously determined50. However, prior pharmacokinetic and efficacy data comparing 200mg BID 
versus 400mg BID in phase I and phase II trials have not shown major differences between the 
two dosing strategies50,51. Notably, the lower dose of 200mg BID led to decreased grade 3-4 
anemia of 6% as compared to 13% in patients treated with 400mg BID51.  
 
 
 
 
 


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Figure 6. Efficacy of intermittent sequential versus concomitant RP-3500 plus olaparib in the 
SUM149PT breast cancer xenograft model (BRCA1-deficient), 
 
 
RP-3500 at 15 mg/kg is 50% of the MTD on a 3 day on/4 day off dosing schedule. The combination 
of low dose RP-3500 administered concomitantly with low dose olaparib given on an intermittent 
schedule led to superior efficacy when compared to either single agent at full dose (Figure 6).  
 
3.11 Rationale for Starting Doses of RP
-3500 and Olaparib  
The currently presented data supports the administration of RP-3500 and olaparib with 
intermittent dosing (3 days per week) and at reduced doses from the previously determined 
monotherapy MTDs. Furthermore, dosages of RP-3500 and olaparib must also account for the 
potential drug-drug interaction between RP-3500 and olaparib as previous in vitro data has shown 
olaparib to be an inhibitor of the two major metabolic proteins for RP-3500, including CYP3A4 
and UGT1A1. Therefore, the proposed starting dose of RP-3500 at 50mg daily and olaparib at 
100mg BID administered with intermittent 2 days per week dosing was based on preclinical PK 
data and prior toxicity experience with both drugs to help reduce toxicity while maintaining 
efficacy.  
 


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3.12 Rational e for Allowing Creatinine Clearance
 (CrCl) Between 45 and 59 mL/min  
In an analysis of 154 solid tumor patients treated with RP-3500, there were small changes in the 
PK clearance of RP-3500 among patients with normal renal function (N=62), mild renal 
impairment (N=49) and moderate renal impairment (N=13) defined as CrCl between 45 and 59 
mL/min (Table 3). However, the analysis is confounded by the lower mean body weights in the 
moderate renal impaired patients, but still supports little effect of renal impairment on the PK of 
RP-3500. 
 
Table 3. PK Clearance of RP-3500 Among Patients with Normal, Mild, and Moderate Renal 
Impairment  
 
Reassuringly, the modest PK effects of renal impairment did not translate to increased observed 
toxicities including anemia, neutropenia and treatment-emergent significant adverse events 
(TESAE) (Table 4, 
 
Table 5, Table 6) 
 
Table 4. Summary Anemia by Renal Function Categories (CrCL) 


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Table 5. Summary Neutropenia by Renal Function Categories (CrCL) 
 
Table 6. Summary TESAE by Renal Function Categories (CrCL) 
 
While Olaparib is affected by CrCl, the package insert for olaparib does not recommend any dose 
modifications for CrCl between 51-80 mL/min.52 If a patient has moderate renal impairment, 
defined as CrCl 31-50mL/min, the package insert recommendation is to decrease Olaparib to 
200mg BID. However, due to the anticipated synergy between RP-3500 and Olaparib, the starting 
dose of Olaparib for this trial is 100mg BID at dose level 1 with a maximum dose of Olaparib at 
150mg BID for dose levels 2 and 3, which are all below the recommended reduced 200mg BID 
for moderate renal impairment. 
4 
STUDY DESIGN 
This is an open-label, multicenter, phase Ib/II study of the combination of camonsertib (RP-3500) 
and olaparib in R/R CLL patients with DDR deficiencies.  
4.1 
Justification for New Dosing Schema and
 Dose Escalation  
At the previous dose level 1, five R/R CLL patients were treated with camonsertib (RP-3500) 
40mg daily and olaparib 100mg BID dosed 3 days per week. One patient met the definition of a 
dose limiting toxicity due to persistent grade 4 thrombocytopenia lasting ≥7 days. Cytopenias 
were the most common AEs with 2/5 (40%) of patients experiencing grade 4 thrombocytopenia 
as per the iwCLL criteria. Grade ≥3 neutropenia occurred in 2/5 (40%) of patients with one patient 
experiencing a grade 3 neutropenic fever outside of the DLT window. 


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In the ongoing parallel ATTACC study (NCT04972110) of combination camonsertib (RP-3500) 
and PARPi combinations (either niraparib or olaparib) in patients with molecularly selected 
cancers (i.e. DDR-deficient solid tumors), similar cytopenias were observed with the 3 days per 
week dosing. However, better tolerance of the combination was observed when patients were 
dosed only 2 days per week. In preliminary data, reduction of the dosing to 2 days per week 
significantly reduced ≥grade 3 toxicities by 5-fold as compared to 3 days per week dosing at 
similar dosages of combination RP-3500 and olaparib. The 2/5 (i.e. 2 days on and 5 days off) 
dosing strategy is supported by previous preclinical data generated in DDR-deficient bladder 
cancer cell lines in which shortening the treatment of the cells to 48 hours had no significant effect 
on the IC50 as compared to continuous dosing (Refer to RP-3500 Investigator Brochure Section 
4.2.1.4.2.1). Furthermore, treating various DDR-deficient solid tumor cell lines with RP-3500 and 
various PARPi dosed with a 2/5 strategy in vitro demonstrated strong synergy with the 
combination treatments (Refer to RP-3500 Investigator Brochure Section 4.2.1.5.1). Given the 
prior clinical experience of RP-3500 and olaparib with the 2/5 dosing strategy in solid tumor 
patients along with the existing preclinical data to support this dosing method, we propose to 
amend the phase Ib of combination RP-3500 and olaparib in R/R CLL patients to be dosed with 
a 2/5 treatment strategy to improve the tolerability of the combination. 
4.2 
Phase Ib  Dose Escalation  
4.2.1 The Phase Ib part of the trial will seek to assess the MTD of camonsertib (RP-3500) in 
combination with olaparib. Given the potential overlapping toxicities of RP-3500 and olaparib, a 
keyboard phase I design, a novel Bayesian method that typically underestimates the MTD,53 will 
be employed. The target toxicity is 30% with an equivalence interval between 25-33% of patients. 
With an anticipated 3 dose levels (DL) and an option for a DL-1, up to 18 patients may be required 
to determine the MTD. A maximum of 12 patients will be treated at a DL.  
The first 5 patients treated at the previous DL1 (camonsertib 40mg daily and olaparib 100mg 
BID dosing 3 days per week) determined that this dosing strategy may not be appropriate for 
R/R CLL patients and reduced dosing may be necessary to increase safety of the combination 
therapy. Therefore, the newly proposed DLs will seek to enroll an additional 18 patients. 
4.2.2 Dose Escalation 
During dose escalation, four DLs of combination therapy of RP-3500 and olaparib may be 
explored (Table 7. Dose levels of RP-3500 and olaparib in phase Ib portion of the trial.). Subjects 
will be enrolled in cohorts of three starting with DL 1. Enrollment will be placed on hold to allow 
for all members of a cohort to complete the Dose Limiting Toxicity (DLT) period. Once all subjects 
in a cohort have completed the defined DLT evaluation period, the assignment of the dose level 
for the following cohort will follow the decision algorithm in Table 8. Dose escalation rules 
according to the keyboard phase I design. Doses may be escalated (E) to the next highest dose 
level, de-escalated (D) to a lower dose level, or stay (S) at the same dose level (Table 8. Dose 
escalation rules according to the keyboard phase I design.).  


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Table 7. Dose levels of RP-3500 and olaparib in phase Ib portion of the trial.  
*Both drugs are given with intermittent dosing of 2 days per week.  
 
 
 
 
 
 
 
As long as there are not any unacceptably (U) high toxicities encountered with the enrolled 
patients as according to the keyboard algorithm, then the trial can continue enrollment in cohorts 
of 3 patients. Each cohort will complete the DLT window at which point it will trigger the Data 
Safety Monitoring Committee (DSMC) and the Principal Investigator of the trial to convene and 
determine the appropriate DL for the following cohort(s). The DSMC and Principal Investigator 
can also make the recommendation to enroll in cohorts of 1-2 patients if a slower enrollment is 
required to ensure the safety of the drug combination. All patients enrolled in these smaller cohorts 
must complete the DLT window prior to the determination of the number of patients to enroll in 
the next cohort and at which DL. Should a DL accumulate enough DLTs so that the keyboard 
algorithm dictates a U, the remaining cohorts will be de-escalated to the next lowest DL and no 
more patients will be treated at the DL with U toxicities. 
Table 8. Dose escalation rules according to the keyboard phase I design.  
Depending on the number of patients treated on the current dose level and the number of dose-
limiting toxicities encountered, the algorithm will dictate dose escalation (E) to the next highest 
dose, de-escalation (D) to the next lowest dose or stay (S) at the current dose level. Should any 
DL encounter an unacceptable (U) toxicity in the decision table, future cohorts will be D to next 
lowest dose and no further patients will be treated at this DL.  
Dose Level  RP-3500 
Olaparib  
-1# 
40mg daily 100mg BID 
1* 
50mg daily 100mg BID 
2* 
80mg daily 100mg BID 
3* 
80mg daily 150mg BID 


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4.2.3 Determination of The MTD and RP2D 
After successful enrollment of 18 patients who have completed the DLT window, then the phase 
Ib portion of the trial will be complete. An exception to this is if any DL enrolls 12 patients and the 
keyboard algorithm dictates to stay at the current dose level. The MTD and RP2D will be 
determined to be the DL in which the 12 patients are enrolled as the chances of additional patients 
treated at the current DL altering the decision table of the keyboard design would be low. 
Therefore, the phase Ib portion of the trial may be completed before the enrollment of 18 total 
patients. If a DL reaches 8 patients and 2 DLTs are noted, the keyboard decision table dictates 
an S at the current DL. The Principal Investigator or DSMC can determine to enroll 4 additional 
patients at the current DL if the 4 additional patients do not put the total number of patients 
enrolled into the phase Ib portion over 18. 
After the phase Ib portion is completed, final DLT rates at each dose level will be estimated by 
isotonic regression54.  The weighted least squares regression model will assume monotonic non-
decreasing DLT rates with increasing dose and use the empirical (observed) DLT rates at each 
DL as responses and DL sample sizes as weights, along with the pool adjacent violators algorithm 
(PAVA) to estimate the DLT rate at each dose level.  Given the DLT estimates for each dose 
level, all tried dose levels that have not been previously declared to be unsafe with a U decision 
according to the keyboard decision table will be considered for the RP2D. With this constraint, 
the MTD will be determined as the dose level with the DLT estimate closest to the target toxicity 
level of 30%.  
Number of Patients Treated At Current Dose Level
 
# of DLTs 
Observed  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
0 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
D 
S 
E 
E 
E 
E 
E 
E 
E 
E 
2 
D 
D 
D 
D 
D 
S 
S 
E 
E 
E 
E 
3 
U 
U 
D 
D 
D 
D 
D 
S 
S 
S 
4 
U 
U 
U 
D 
D 
D 
D 
D 
D 
5 
U 
U 
U 
U 
U 
D 
D 
D 
6 
U 
U 
U 
U 
U 
U 
D 
7+ 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
U 


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Each dose level may enroll approximately 3 to 12 subjects in order to further inform RP2D 
decision. Enrollment to the highest open dose level will be prioritized if multiple dose levels are 
open for enrollment. The RP2D will be selected with approval from all investigators and the DSMC 
after considering the cumulative safety, PK/Pd (as available) and efficacy data from subjects 
treated in dose escalation. 
4.2.4 Definition of Dose Limiting Toxicities 
DLTs will be assessed for each patient within the DLT window. The DLT window is defined as the 
time from Cycle 1 Day 1 to Cycle 1 Day 21. Common terminology criteria for adverse events 
(CTCAE) v5.0 will be used to grade all adverse events (AE) and to provide management 
guidelines for administrational toxicity. Any of the following AEs which cannot be incontrovertibly 
attributed to CLL or CLL disease progression will be defined as a DLT. 
General  
a. Treatment delays > 21 days. 
b. Any grade 5 event. 
Non-hematologic  
a. Any grade ≥ 4 event. 
b. Any grade ≥ 3 non-hematologic toxicity with the following exceptions: 
i. 
Grade 3 fatigue, asthenia, anorexia, fever, or constipation. 
ii. 
Grade 3 nausea, vomiting or diarrhea not requiring tube feeds, TPN or 
hospitalization. 
iii. 
Grade 3 or 4 non-clinically significant and transitory laboratory abnormalities that 
resolve to ≤ grade 1 or baseline within 7 days, except for any possible Hy’s Law 
event (Refer to 8.3.2) 
iv. 
Alopecia 
v. 
Tumor lysis syndrome not requiring dialysis 
vi. 
DVT responsive to anticoagulation 
 
Hematologic  
a. For patients with baseline/screening absolute neutrophil count (ANC) 
≥1000/mm3, grade 4 neutropenia [ANC <500/mm3] not responsive to optimal 
supportive care or G-CSF administration lasting ≥5 days. For patients with 
baseline/screening ANC <1000/mm3, DLT here is defined as a ≥75% reduction 
from baseline ANC not responsive to optimal supportive care or G-CSF 
administration lasting ≥5 days. 
b. Any grade febrile neutropenia.  


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c. For patients with baseline/screening platelet count ≥100,000/mm3, grade 4 
thrombocytopenia (platelet count <25,000/mm3) lasting ≥7 days. For patients 
with baseline/screening platelet count <100,000/mm3, DLT here is defined as a 
≥75% reduction from baseline platelet counts lasting for ≥7 days. 
d. Grade ≥3 thrombocytopenia-associated bleeding. 
 
Subjects will be considered eligible for DLT assessment if they have received at least 1 dose of 
RP-3500 and 1 dose of olaparib. 
4.2.5 Consideration of Alternative Dosing Strategies 
Alternative dosing strategies including extended intermittent dosing will be considered should any 
dose level be deemed unacceptably toxic. A meeting between all investigators, the sponsor, and 
DSMC will be held to determine and approve alternative DLs. Any alternative DLs evaluated will 
only do so with an amendment to the protocol and appropriate justification. 
If a majority of the review committee deem the combination too toxic at any DL, then the trial may 
be terminated at that time. 
4.2.5.1 Dose Level -1 is Deemed Unacceptable Toxicity 
If the number of DLTs incurred at DL-1 is deemed U by the keyboard design decision table, 
alternative dosing schedules and strategies will be considered. These include adding additional 
DLs in which RP-3500 is dosed at either 20mg, 30mg, 40mg, or 50mg daily. Depending on the 
DLTs encountered at DL-1 and if these were attributed to either RP-3500 or olaparib 
administration, olaparib for these additional DLs can be dosed between 100-200mg BID. The new 
DLs may have either similar intermittent dosing schedule of the combination with 2 days on and 
5 days off or an alternative dosing strategy of the combination of 2 weeks on and 1 week off. 
Other considerations would include a 28 day cycle in which the dosing would alternate between 
the 4 weeks (i.e. first week on, second week off, third week on, fourth week off) with dosing being 
2-3 days in the “on” weeks. 
4.2.5.2 Exploration of Extended Intermittent Dosing 
Should DLTs occur at at any DL so that the keyboard algorithm deems that DL unacceptably 
toxic, an extended intermittent dosing schedule can be considered. While subsequent patients 
would enroll with the same RP-3500 and olaparib dosages at the current DL, an extended 
intermittent dosing schedule can be explored in which patients would dose for 2 weeks on and 
then have a 1 week rest period within a 21-day cycle. In the 2 weeks that patients dose, RP-3500 
and olaparib will be administered 2 days during the week with 5 days off (Table 10). 
Table 9. Modification of Dosing Schedule for Toxicity with Every Week Dosing 
Dose Level  
RP-3500 
Olaparib  
Dosing Schedule  
-1 
40mg daily 
100mg BID 
2 days on/5 days off, every week  


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-1A 
40mg daily 
100mg BID 
2 days on/5 days off; 2 weeks on/1 week off 
1 
50mg daily 
100mg BID 
2 days on/5 days off, every week  
1A 
50mg daily 
100mg BID 
2 days on/5 days off; 2 weeks on/1 week off 
2 
80mg daily 
100mg BID 
2 days on/5 days off, every week  
2A 
80mg daily 
100mg BID 
2 days on/5 days off; 2 weeks on/1 week off 
3 
80mg daily 
150mg BID 
2 days on/5 days off, every week  
3A 
80mg daily 
150mg BID 
2 days on/5 days off; 2 weeks on/1 week off 
If patients enrolled at the extended intermittent dosing DLs clear a DL, dose escalation may 
continue but must follow the outlined A DLs in Table 9. Modification of Dosing Schedule for 
Toxicity with Every Week Dosing(i.e. DL -1A, DL 1A, DL 2A, DL 3A).  
 
 
 
 
 
 
4.2.5.3 Escalation Beyond DL3 
If enrollment of patients reaches DL3 and this DL is deemed safe, consideration for a DL4 in which 
RP-3500 is dosed at 120mg daily and olaparib is dosed at 150mg BID (2 days per week) will be 
considered. In this case, 6 additional patients will be added to the phase Ib cohort for a maximum 
of 24 patients. 
4.2.5.4 Continuous Dosing 
In any of the original and alternative DLs, continuous RP-3500 and/or olaparib dosing (i.e. no 
days off) may be explored pending the PK, PD and toxicity assessments, and with the approval 
of the DSMC and amendment to the protocol. 
4.2.5.5 Intra-patient Dose Escalation 
At the discretion of the treating investigator, phase Ib patients enrolled at a lower DL may have 
their doses of camonsertib (RP-3500) and/or olaparib escalated to the next highest DL that has 
cleared the DLT window and deemed acceptably safe by the DSMC. Patients may not escalate if 
they have encountered a decrease in dosages or dose schedule due to treatment-related AEs, or 
have not been able to maintain their assigned DL dosages and dosing schedule for at least 6 
weeks. However, if a patient required a dosing schedule modification (i.e. reduction from every 
week dosing to 2 weeks on/1 week off) and has not experienced significant treatment-related AEs 
grade >2 on the new dosing schedule for at least 6 weeks, and the next cleared DL is also a 


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dosing schedule of 2 weeks on/1 week off, the patient may still escalate their dosages of RP-3500 
and/or olaparib to the newly cleared DL. 
4.3 
Phase II Dose Expansion  
After completion of the phase Ib portion and assignment of the RP2D, continuous enrollment of 
patients may commence into the phase II dose expansion portion. All patients enrolled at the 
RP2D during the phase Ib dose-escalation portion of the trial can be carried over into the phase 
II analysis. The maximum number of patients that can be carried over from the dose escalation 
to the dose-expansion portion is 12. 
The phase II dose expansion will consist of two separate cohorts of subjects: an enrichment cohort 
and a cohort for all other eligible subjects. All subjects enrolled into the enrichment cohort must 
have a del(11q) and/or ATM mutation. Eight subjects will be enrolled into the enrichment cohort 
and 16 will be enrolled into the second cohort for a total phase II cohort of 24 patients. 
4.4 
Study Duration  and Sample Size  
With cohorts of 3 patients and possible early completion of the dose-escalation due to a DL 
accruing 12 patients, then the minimum time to accrue 4 cohorts is 4 months. Due to potential 
delays in patient enrollment and variability in dose escalation cohort size, the maximum 
enrollment time frame for the dose escalation portion is anticipated to be 24 months. Expansion 
at the RP2D is anticipated to be between 6-12 months as a portion of the dose escalation cohort 
treated at the RP2D will be rolled into the expansion cohort. Therefore, the total study duration is 
between 12-36 months, which is inclusive of the phase Ib and phase II durations.  
On average, we expect 33 patients to be enrolled, assuming that 9 patients in the phase Ib portion 
will be treated at the MTD and rolled into the dose expansion phase. If the dose escalation portion 
enrolls patients only at the RP2D and all of these patients are rolled into the dose-expansion 
cohort, then the minimum number of patients required would be 24 for the entire trial. The 
maximum number of patients required would be 39 assuming that only 3 patients roll over from 
the dose escalation to the dose expansion. 
4.5 
End of Study  
A subject is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Events  
The study will end when the last subject completes the last visit or last contact, discontinues from 
the study, or is lost to follow-up, whichever occurs first. In addition, the sponsor may terminate 
the study at any time. If at any time, the sponsor terminates the study any subjects receiving 
clinical benefit from the study intervention may roll over to an expanded access protocol to ensure 
continued access to the study medication. 
 
4.5.1 Continuation of Study Protocol Treatment Beyond 18 Cycles 
If a subject completes 18 cycles of study protocol treatment and is still deriving clinical benefit, 
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indefinitely. Patients may discontinue follow up and treatment as per section 6.9.1 and discontinue 
the study as per section 6.9.2. All required “EOT” assessments should be performed at the 
completion of C18D21 including laboratory, imaging and bone marrow assessments. The post-
treatment “follow-up” 28 days later is not required.  
After cycle 18, the patient should be monitored every 1-3 cycles with physical exam, ECOG PS, 
vital signs, height/weight and laboratory assessments that are required on previous day 1s (e.g. 
cycle 4 day 1). Camonsertib (RP-3500) and olaparib may be dispensed to the patient in 1-3 month 
allotments depending on the intended follow up as determined by the treating investigator. Repeat 
imaging and bone marrow biopsies are not mandatory during this extended treatment period and 
should be performed as clinically indicated, following the step-wise approach outlined in footnote 
20 of the Schedule of Events. 
4.6 
Duration of Follow Up  for PFS  and DoR  
Patients will be followed for PFS until progression of disease noted or death, whichever occurs 
first.  Patients will be followed for DoR until progression is noted from the best response, start of 
a new therapy, or death from any cause. Refer to section 1.1 for long-term follow up time points. 
In the first year, patients will be followed every 3 months. Between years 2 to 5, the patient will be 
followed every 3-6 months at the discretion of the treating provider. After 5 years, the patient will 
be followed every 3-12 months at the discretion of the treating provider. Patients removed from 
study for unacceptable adverse event(s) will be followed until resolution or stabilization of adverse 
event.  Follow up data will be required unless consent is withdrawn. Overall survival follow up for 
patients who have progressed will be completed according to section 6.9.4. 
5 
STUDY POPULATION 
Potential study participants must meet all inclusion criteria and no exclusion criteria to be deemed 
eligible for trial participation. To ensure subject safety, all subjects must be deemed eligible at the 
time of study registration and must continue to meet eligibility criteria up to cycle one day one 
dosing. This eligibility checklist is used to determine subject eligibility and will be filed with the 
enrolling investigator’s signature in the subject research chart. 
5.1 
Inclusion Criteria  
5.1.1 _____ Diagnosis of CLL according to the NCI/IWCLL criteria. 
This includes previous documentation of: 
a. Biopsy-proven small lymphocytic lymphoma/CLL 
OR 
b. Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all 
of the following: 
1. Peripheral blood monoclonal B cell population of greater than 
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2. Immunophenotype consistent with CLL defined as: 
 
The predominant population of lymphocytes share both B 
cell antigens [CD19, CD20 (typically dim expression), or 
CD23] as well as CD5 in the absence of other pan-T-cell 
markers (CD3, CD2, etc). 
 
Clonality as evidenced by κ or λ light chain restriction 
(typically dim immunoglobulin expression) 
c. Negative FISH analysis for t(11;14)(IgH/CCND1) on peripheral blood or 
tissue biopsy (e.g. marrow aspirate), or negative immunohistochemical 
stains for cyclin D1 on involved tissue biopsy (e.g. marrow aspirate or 
lymph node biopsy). 
5.1.2 _____ Repeat testing of somatic mutations and FISH analysis must be performed by a 
CLIA certified laboratory after progression is noted from most recent line of therapy and within 6 
months of screening.  Primary CLL cells must harbor at least one of these abnormalities:  
 
Somatic gene mutation testing shows mutation(s) in TP53, ATM, SF3B1, XPO1 
and/or POT1 
 
Cytogenetic FISH analysis shows deletion 17p13 and/or deletion 11q22.3 
5.1.3 _____ Relapsed or refractory after at least 2 prior lines of therapy, and in the opinion of 
the treating Investigator are either not eligible for other approved therapies or no approved 
therapies are expected to have sustained therapeutic benefit. 
5.1.4 _____ Patient in need of treatment or change in treatment per iwCLL criteria. 
i. Patients on BTK, PI3K or BCL2 inhibitors may enroll without meeting 
iwCLL criteria for treatment as long as there is clinical evidence of 
progression (i.e. increasing lymphocytosis, worsening 
anemia/thrombocytopenia attributable to CLL disease progression, 
increasing lymphadenopathy, or worsening patient symptoms) and 
require change in treatment at the discretion of the treating provider. 
Patients must still meet all other inclusion/exclusion criteria for enrollment 
including appropriate washout periods (5.2.2) and relapsed disease after 
2 prior lines of therapy with no other approved therapies that are 
expected to have sustained therapeutic benefit (5.1.3). 


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5.1.5 _____ Age ≥18 years 
5.1.6 _____ ECOG performance status between 0-2 
5.1.7 _____ Expected life expectancy of at least 12 months per the investigator. 
5.1.8 _____ The following laboratory or clinical values obtained ≤ 42 days prior to enrollment: 
 
Absolute neutrophil count ≥1000/µL (G-CSF support is allowed) unless 
documented bone marrow involvement of CLL 
 
Platelets of ≥50K/µL unless documented bone marrow involvement of CLL 
 
Creatinine Clearance (CrCl) ≥ 45 mL/minute as measured by a 24 hour urine 
collection or calculated by the Cockcroft-Gault Formula: 
 Males: 
(140−𝑎𝑔𝑒)×𝑤𝑒𝑖𝑔ℎ𝑡[𝑘𝑔]
𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔
𝑑𝐿]×72 
 Females: (
(140−𝑎𝑔𝑒)×𝑤𝑒𝑖𝑔ℎ𝑡[𝑘𝑔]
𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔
𝑑𝐿]×72) × 0.85  
 
Total bilirubin ≤ 1.5 x institutional ULN unless due to Gilbert’s disease. For those 
patients with previous history of Gilbert’s disease, a direct bilirubin should be 
performed and must be <1.5mg/dL. 
 
SGOT (AST)/SGPT (ALT) ≤3.0 x the institutional ULN 
 
QTcF ≤470 msec 
 For patients with prolonged AT interval due to bundle branch block, a 
“corrected value” ≤470 msec and confirmation by cardiologist that patient 
is asymptomatic and that no other cardiac conduction or cardiac 
abnormality is present would pose any safety issues for the patient. 
 Recommended correction of QT for patients with bundle branch block are 
as follows: Patient’s QRS is 160 msec, and the measured QT is 510 
msec. As the normal QRS is ~120 msec, subtract 120 msec from the 
measured QRS of the patient (160-120 = 40 msec) and then subtract this 
result from the measured QT (510-40=470 msec). 
 
Pulse oximetry reading of ≥90% on room air 


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5.1.9 _____ Able to adhere to study visit schedule and other protocol requirements 
5.1.10 _____ Patients must be able to swallow capsules 
5.1.11 _____ Patients must be able to receive xanthine oxidase inhibitor and/or rasburicase for 
tumor lysis syndrome prophylaxis. 
5.1.12 _____ Patients with a history of hepatitis B (surface antigen or core antibody-positive 
and PCR positive) must take lamivudine or equivalent drug during study therapy and for one 
year after completion of all therapy.  Patients on IVIG who are core antibody-positive but PCR 
negative are not mandated to take prophylaxis. 
5.1.13 _____ Patients who are HIV+ are eligible under the following circumstances: 
 
Undetectable HIV viral load (laboratory value obtained within the last 6 months 
prior to enrollment) 
 
CD4 count ≥200 (laboratory value obtained within the last 6 months prior to 
enrollment) 
 
Actively taking antiretroviral therapy (ART) 
 
Current ART therapy cannot have significant interactions with RP-3500 or 
Olaparib (Refer to Appendix 5).  If current medications do interact, patients 
should receive alternative ART. 
5.1.14 _____ Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior 
cancer therapy, unless considered clinically not significant by the treating investigator. 
 
5.1.15 _____ Female patients capable of reproduction or males who have partners capable of 
reproduction must agree to the use of an effective contraceptive method during the course of 
the study and for 6 months following the completion of their last 
treatment. 
 


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5.1.16 _____ Females of childbearing potential must have a negative serum β-Hcg pregnancy 
test result within 3 days of the first study dose.  Female patients who are surgically sterilized or 
who are >45 years old and have not experienced menses for >2 years may have β-Hcg 
pregnancy test waived. 
5.2 
Exclusion Criteria  
5.2.1 _____ Patients who are currently receiving any other investigational drug. Patients who 
are or have received therapies for the prevention, treatment or management of COVID-19 under 
the FDA emergency use authorization are allowed to enroll. 
5.2.2 _____ Patients who have received: 
 
Radiation or chemotherapy ≤2 weeks prior to registration. 
 
Immunotherapy or targeted therapy ≤2 weeks prior to registration. 
i. Patients currently on BCR pathway antagonists (i.e. BTK and PI3K 
inhibitors, etc) require a 2 day wash out period prior to starting 
combination therapy with RP-3500 and olaparib as these subjects 
progress quickly after treatment discontinuation. 
 
Strong CYP3A inhibitors or inducers, p-glycoprotein inhibitors, or BCRP inhibitors 
within five half-lives or 14 days of registration, whichever is shorter (See 
Appendix 5). 
5.2.3 _____ Prior ATR inhibitor use, but prior PARP inhibitor use for any reason is allowed on 
study. 
5.2.4 _____ Major surgery 4 weeks prior to C1D1 or who have not fully recovered from major 
surgery. 
5.2.5 _____ Evidence of active Richter’s Transformation 
5.2.6 _____ Disease states requiring steroids (e.g. adrenal insufficiency, autoimmune 
conditions) are allowed as long as the steroid dose is ≤10mg of prednisone or equivalent dose 
of another steroid. Steroids premedications to prevent iodine contrast allergy for CT scans are 
allowed. 
 


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5.2.7 _____ Patients who have undergone autologous stem cell transplant ≤4 weeks or 
allogeneic stem cell transplant ≤12 weeks prior to cycle 1 day 1 or have active graft-versus-host 
disease are excluded. 
5.2.8 _____ Patients who have active, clinically significant hepatic impairment (≥ moderate 
hepatic impairment according to the NCI/Child-Pugh classification) 
5.2.9 _____ Prior history of another malignancy except for the following:   
 
Patients with current history of basal or squamous skin carcinoma, cervical 
carcinoma in situ, localized breast cancer requiring hormonal therapy, or 
localized prostate cancer (Gleason score <6) are allowed.  
 
Previously treated malignancies (with chemotherapy, radiation, and/or 
surgery) currently deemed to have been in complete remission for at least 24 
months. 
5.2.10 _____ Patients with active known central nervous system (CNS) involvement of CLL. 
Patients with a history of CNS CLL now in remission are eligible for the trial. 
5.2.11 _____ Patients with uncontrolled concurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, extensive bilateral interstitial lung 
disease, unstable angina pectoris, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
Patients with a history of pneumonitis or pulmonary disease that could 
predispose them to development of ILD and/or underlying respiratory conditions 
should be excluded. 
5.2.12 _____ Known prior severe hypersensitivity to RP-3500, olaparib, or any component in its 
formulations (NCI CTCAE v5.0 Grade ≥ 3). 
5.2.13 _____ Female patients who are pregnant or actively breast feeding 
5.2.14 _____ Patients with conditions significantly affecting gastrointestinal function including, 
but not limited to: 
 
Significant resection of the stomach or small bowel 
 
Symptomatic inflammatory bowel disease 
 
Partial or complete bowel obstruction 
5.3 
Registration  
Subjects must meet all of the eligibility requirements before registration. Study-related screening 
procedures can only begin once the subject has signed the consent form. Subjects must not begin 
protocol treatment prior to registration. 
Treatment should start within 14 days after registration. 


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To register eligible subjects on study, complete a Clinical Trials Office Subject Registration Form 
and submit to CTORegistrations@hci.utah.edu. 
For 
sites 
outside 
of 
Huntsman 
Cancer 
Institute, 
submit 
registration 
forms 
to 
MultisiteRegistrations@hci.utah.edu  
5.4 
Life Style Considerations
 
5.4.1 Diet 
Due to CYP3A4 interactions, subjects will be advised to avoid grapefruit, Seville oranges, 
pomelos, and star fruit including products containing these fruits (e.g. juices, jams, marmalades, 
etc.). 
5.4.2 Contraception 
Due to the unknown abortifacient and teratogenic effects of RP-3500 and olaparib, a form of highly 
effective contraception is required for the duration of study therapy. Female subjects of 
childbearing potential must use a form of highly effective contraception from the start of study 
therapy until 6 months after the last dose of study therapy. Male subjects with a partner of 
childbearing potential must agree to use a method of highly effective contraception from the start 
of study therapy until 6 months after the last dose of study therapy.  
Acceptable highly effective contraceptive methods include: 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Intra-uterine devise (IUD) or hormone-releasing system (IUS) 
 
Any hormonal (estrogen combined with progesterone or progesterone alone) 
contraception associated with inhibition of ovulation: implanted, oral, intravaginal, 
transdermal, or injectable. 
 
Spermicide with a compatible barrier method (i.e. diaphragm, sponge, or male or female 
condoms). 
 
Abstinence from heterosexual intercourse. 
It is unknown whether RP-3500 and olaparib can produce drug transfer through seminal fluid. 
Therefore, male subjects must agree to use a condom during any form of intercourse from the 
start of study therapy until 6 months after the last dose of study therapy.  
5.5 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical trial but do 
not meet subject eligibility criteria. These subjects will not be entered into the study or begin study 
intervention. However, minimal information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements. Minimal information includes, but may not be limited to, demography, 
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screening, but prior to being deemed ineligible. Adverse events and SAEs will not be collected 
after a subject is deemed ineligible.  
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened at the Investigator’s discretion.  
5.6 
Strategies for Recruitment
 
Investigators will identify potential subjects in the setting of their outpatient clinics. This study will 
be posted on clinicaltrials.gov for help in recruitment. Investigators will perform local and regional 
outreach to patients and physicians. Furthermore, we will enlist the help of patient education and 
advocacy forums such as national cooperative groups, Lymphoma Research Foundation, The 
CLL Society and Leukemia & Lymphoma Society for advertisement of the trial. 
5.7 
Number of Study Sit es 
This is a two-institution study including The University of Utah/Huntsman Cancer Institute (Salt 
Lake City, UT) and MD Anderson Cancer Center (Houston, TX). 
If trial recruitment is anticipated to be greater than the expected maximum of 36 months, then 
additional CLL specialty centers will be asked to participate in this trial. 
6 
STUDY INTERVENTION 
6.1 
Administration Schedule
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient’s CLL. 
Regimen Description  
Agent 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
RP-3500 
Take with 8 oz of water at 
approximately the same 
times each day (±2 hours) 
Capsule* 
Oral 
Once daily; 
intermittent weekly 
dosing of 2 days on 
and 5 days off 
21 days (3 
weeks) 
Olaparib 
Take with 8 oz of water at 
approximately the same 
times each day (±2 hours) 
Capsule* 
Oral 
Twice daily; 
intermittent weekly 
dosing of 2 days on 
5 days off 
* Doses as appropriate for assigned dose level 
Study medications should be taken at approximately the same time every day. Study medication 
should not be crushed, chewed, or altered in any way. Subjects should not take extra 
medication for any reason nor should they re-administer in the case of vomiting after 


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administration. If a dose is missed outside of the dosing window, the dose should not be made 
up but rather dosing should continue at their regularly scheduled time. 
6.1.1 Preparation and Dispensing 
The investigator or qualified personnel will prepare and dispense all investigational supplies. 
Subjects will be dispensed enough medication to last a full cycle of both study medications. 
Appropriate records will be kept to accurately show all dispensing activates and Investigational 
Product (IP) will be supplied only to subjects deem eligible for study therapy. IP may not be 
dispensed to subjects who have not been enrolled in the trial.  
6.1.2 Accountability and Compliance 
Information pertaining to study drug compliance (i.e., date time, and dose) will be recorded by 
subjects on the drug diary (see Appendix 3) and recorded in the corresponding electronic case 
report form (eCRF) by the study team. A member of the study team will review subject drug 
compliance at the end of each cycle and provide subject re-education as required. Any reason for 
non-compliance will be documented in the subject’s research chart and the corresponding eCRF. 
At the discretion of the principal investigator, a subject may be discontinued from the trial for non-
compliance with study visits or study drug. 
Subjects will be required to return any unused medication or empty bottles at the end of every 
cycle. Excess or unused study drug should be returned to the investigative site for accounting 
and destroyed in accordance with GCP after drug accountability has been performed. The total 
number of tablets dispensed, returned, and documented as taken will be reconciled to support 
drug accountability. Treatment compliance will be calculated and recorded separately for each 
drug. It will be recorded as a percentage defined as the number of doses taken divided by the 
expected number of doses taken multiplied by 100%. 
6.2 
Olaparib  
6.2.1 Investigational Product Supplies 
Olaparib will be supplied by Repare Therapeutics as either 150mg or 100mg tablets. 
• 150 mg: green to green/grey, oval, bi-convex, film-coated, with debossment ‘OP150’ on one 
side and plain on the reverse side. 
• 100 mg: yellow to dark yellow, oval, bi-convex, film-coated, with debossment ‘OP100’ on one 
side and plain on the reverse side. 
Olaparib will be stored at 20ºC to 25ºC (68ºF to 77ºF), excursions permitted to 15ºC to 30ºC 
(59ºF to 86ºF). Tablets will be stored in original bottle to protect from moisture. 
The Principal Investigator will ensure appropriately trained and delegated personnel will receive, 
inventory, and stored all investigational products per applicable laws and regulations. 


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6.3 
Camonsertib ( RP-3500)  
6.3.1 Investigational Product Supplies 
RP-3500 will be supplied by Repare Therapeutics as capsules containing 5 mg or 40 mg (free 
base equivalent) of RP-3500 hydrogen sulfate salt. Capsules are packaged in induction-sealed 
HDPE bottles fitted with child-resistant polypropylene caps. The study drug should be stored in 
the original bottles tightly closed in a dry place at 15 to 25°C (59 to 77°F). The capsules should 
not be frozen. 
6.4 
Dose Interruptions   
Dose interruptions for study treatment-related AEs are allowed as per the dose modification 
recommendations in Section 6.6. In addition to dose interruption, the need for a dose reduction 
at the time of treatment resumption should also be considered based on the dose modification 
recommendations. If a toxicity-related dose delay lasts for >28 days, treatment will be 
discontinued permanently and the subject should be removed from study treatment. If a subject 
requires a dose hold for > 28 days for a non-treatment-related adverse event or situation (i.e. 
radiation therapy or COVID-19 infection) the subject may continue on study only after approval 
and discussion with the Principal Investigator and Medical Monitor. 
All doses that were missed for any reason will not be replaced. 
6.5 
Dose Reductions  
In dose-escalation, toxicities that occur within the DLT window that are deemed DLTs (Section 
4.1.3 Definition of Dose Limiting Toxicities) will result in protocol removal.  Adverse events that 
are not defined as DLTs, or occur after the DLT window, or occur in patients enrolled in the dose-
expansion cohort may lead to dose delays and modifications as detailed in section 6.6.  No dose 
reduction below RP-3500 20mg daily and olaparib 100mg BID will be allowed.  Should the protocol 
dictate a dose reduction of olaparib below 100mg BID and/or RP-3500 below 20mg daily, the 
patient will be taken off of the protocol therapy. While these are suggested dosing schedule 
modifications and dosage reductions, the optimal dosing and dosing schedule for each patient 
should be individualized, and may not always fall into a step-wise fashion. Consultation with the 
study PI and medical monitor is recommended to determine the optimal dosing for each patient 
after significant AEs. 
6.6 
Dose Modifications and Supportive Care Guidelines  
Subjects experiencing AEs attributed to study drug may undergo dose modifications for toxicity 
management. Dose modification guidelines are provided below for AEs considered to be related 
to study medication.  
6.6.1 Dosing Schedule Modifications 
The dose modifications will first alter the dosing schedules. The dosages of camonsertib (RP-
3500) and olaparib will remain the same as the dose to which the patient was originally assigned: 
 
 


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Table 10.: Dosing Schedule Modifications
 
Dose L evel 
Schedule (21 -Day Cycles)  
Camonsertib (RP -3500) and 
Olaparib dosing  
Starting  
3 weeks on 
2 days on/5 days off 
-1 
2 weeks on/1 week off 
2 days on/5 days off during 
dosing weeks 
-2 
1 week on/2 weeks off 
3 days on/4 days off during 
dosing weeks 
 
Should the patient require further dose reductions for toxicities, decreases in either camonsertib 
and/or olaparib dosages can be considered while maintaining the current dosing schedule or 
concurrently with a dosage decrease and a change in the dosing schedule. The study PI and 
medical monitor should be contacted for help in determining optimal dosing and dosing schedule 
for the patient. Some example patient scenarios are presented below: 
 
Patient experiences grade 3 neutropenic fever for a second time while receiving 
camonsertib (RP-3500) 50mg daily and olaparib 150mg BID on a dosing schedule of 2 
days per week every week (i.e. no off weeks). Dose reduction of camonsertib to 40mg 
daily and olaparib to 100mg BID can be considered while maintaining the 2 days per week 
every week (i.e. no off weeks) dosing schedule. 
 
Patient experiences grade 4 neutropenic fever while receiving camonsertib (RP-3500) 
50mg daily and olaparib 150mg BID on a dosing schedule of 2 days per week every week 
(i.e. no off weeks). Dose reduction of camonsertib to 40mg daily and olaparib to 100mg 
BID along with reduction of the dosing schedule to 2 weeks on/1 week off may be 
considered while maintaining the 2 days per week treatment during the dosing/on weeks. 
6.6.2 Drug Dosage Modifications 
After dosing schedule modifications, dosage reductions of either camonsertib and/or olaparib can 
considered independently or concurrently with dosing schedule modifications. If either 
camonsertib (RP-3500) or olaparib requires reductions to below DL 1 for toxicity management, 
study therapy will be discontinued: 
Table 11. Dose Reduction Levels 
Dose 
Level  
Camonsertib ( RP-3500) 
1 
20mg daily 
2 
30mg daily 


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3 
40mg daily 
4 
50mg daily 
5 
80mg daily 
 
Dose Level  Olaparib  
1 
100mg BID 
2 
150mg BID 
 
6.6.3 Hematologic and Infectious Toxicities 
Optimal supportive care should be offered to the patient in order to mitigate toxicities.  Where 
appropriate, this includes administration of G-CSF, GM-CSF and blood/platelet transfusions as 
per institutional guidelines.  At the start of each cycle, hold therapy until ANC ≥500/mm3 and 
platelet count is ≥25,000/mm3. Lymphopenia is an expected toxicity of CLL treatments and 
therefore should be graded and recorded as per CTCAE v5.0,
 but treatment holds and dose 
changes are not needed.  
 
This study will utilize the 2018 IWCLL grading scale for hematologic adverse events in patients 
with baseline platelet count <100,000/mm3 and/or baseline hemoglobin less than the lower limit 
of normal55.  Grading of ANC is at the nadir within the cycle, and patients who have an ANC <1 x 
109/L before therapy will not be evaluable for toxicity. These criteria account for baseline 
cytopenias secondary to CLL and are detailed in Table 12 below. 
 
Table 12. iwCLL Hematologic Grading 
Grade 
 
Decrease in platelets or hemoglobin 
from baseline value, % 
Absolute neutrophil count* 
(nadir) x 109/L 
0 
 
No change to 10 
≥2 
1 
 
11-24 
≥1 and <2 
2 
 
25-49 
≥1 and <1 
3 
 
50-74 
≥0.5 and <1 
4 
 
≥75 
<0.5 


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*If the absolute neutrophil count (ANC) reaches <1 × 109/L, it should be judged to be 
grade 3 toxicity. Other decreases in the white blood cell count or in circulating 
granulocytes are not to be considered because a decrease in the white blood cell 
count is a desired therapeutic end point. A gradual decrease in granulocytes is not a 
reliable index in CLL for stepwise grading of toxicity. If the ANC was <1 × 109/L before 
therapy, the patient is not evaluable for toxicity referable to the ANC. The use of G-
CSF is irrelevant for the grading of toxicity, but should be documented. 
 
The order in which dose reductions will occur will be change in dosing schedule (Table 10.: 
Dosing Schedule Modifications) with either sequential (preferred) or concurrent changes in drug 
dosages (Table 11). If drug dosage changes are required, the order in which dose reductions will 
occur will be camonsertib (RP-3500) first followed by olaparib if the AE continues to occur. If at 
any time a dose reduction would leave camonsertib (RP-3500) or olaparib doses less than DL 1 
(Table 11. Dose Reduction Levels), the patient will be taken off protocol. Treatment delays for 
adverse events exceeding 21 days will lead to protocol removal. If reduction of the dosing 
schedule and/or drug doses resolves the patient’s toxicity to grade ≤1 for at least 3-6 weeks, 
increasing camonsertib (RP-3500) and/or olaparib back to the prior dose or dosing schedule is 
permitted after discussion with the study PI. 
 
Table 13. Management and dose modification guidelines for hematologic toxicities encountered 
with combination camonsertib (RP-3500) and olaparib. 
Event Name  
Neutropenia  
Grade of Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for 
Olaparib  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
No change in dose 
No change in dose 
Grade 4 
Hold until ANC is ≥1000/mm3. G-
CSF administration is 
recommended. At first occurrence, 
no change in dose or dosing 
schedule. If toxicity recurs, follow 
reductions in dosing schedule and 
drug dosages as per sections  
6.6.1 and 6.6.2 only if grade 4 
neutropenia lasts ≥7 days with 
optimal supportive care. 
Hold until ANC is ≥1000/mm3. G-
CSF administration is 
recommended.  At first 
occurrence, no change in dose or 
dosing schedule. If toxicity recurs,  
follow reductions in dosing 
schedule and drug dosages  as 
per sections 6.6.1 and 6.6.2 only if 
grade 4 neutropenia lasts ≥7 days 
with optimal supportive care and 


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RP-3500 dosage already 
decreased for the same toxicity. 
Only for patients with baseline ANC ≥1000. For patients with baseline ANC <1000, hold until 
ANC 500/mm3 
Event Name  
Thrombocytopenia  
Grade of Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for 
Olaparib  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until platelets ≥50,000/mm3.  
At first occurrence, no change in 
dose or dosing schedule.  If 
toxicity recurs, follow reductions in 
dosing schedule and drug dosages  
as per sections 6.6.1 and 6.6.2. 
Hold until platelets ≥50,000/mm3.  
At first occurrence, no change in 
dose or dosing schedule.  If 
toxicity recurs, follow reductions in 
dosing schedule and olaparib 
dosages  as per sections 6.6.1 and 
6.6.2 if RP-3500 dosage already 
decreased for the same toxicity. 
Grade 4 
Same management as grade 3 
Same management as grade 3 
Only for patients with baseline platelets ≥100,000/mm3. For patients with baseline platelets 
<100,000/mm3, hold until platelets have recovered to at least 50% of baseline value. 
Event Name  
Neutropenic Fever  
Grade of Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for 
Olaparib  
Grade 3 
Hold until resolution of toxicity. G-
CSF administration required. At 
first occurrence, no change in 
dose or dosing schedule.  If 
toxicity recurs, follow reductions in 
dosing schedule and drug dosages  
as per sections  6.6.1 and 6.6.2. 
Hold until resolution of toxicity.   G-
CSF administration required. At 
first occurrence, no change in 
dose or dosing schedule.  If 
toxicity recurs, follow reductions in 
dosing schedule and olaparib 
dosages  as per sections  6.6.1 
and 6.6.2 if RP-3500 dosage 
already decreased for the same 
toxicity. 


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6.6.4 Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS) has been associated with the treatment of CLL and other B-cell 
neoplasms, including venetoclax treatment which requires a dose escalation of the drug over 5 
weeks to mitigate TLS risk56. It is unknown whether combination RP-3500 and olaparib will induce 
TLS upon initiation of treatment. Therefore, TLS prophylaxis with a xanthine oxidase inhibitor will 
be administered at least 72 hours prior to C1D1 and during the first cycle of study therapy. 
TLS blood chemistry monitoring are mandated at screening, C1D1, C1D2, C1D3, C1D8, C1D15, 
and C2D1. After which, TLS monitoring is at the discretion of the treating provider. If rasburicase 
is being considered for the treatment of hyperuricemia, it is recommended to check for red blood 
cell levels of glucose-6-phosphate dehydrogenase (G6PD) as rasburicase administration in 
G6PD-deficient patients may cause severe hemolysis. 
For blood chemistry changes or symptoms suggestive of TLS in cycle 1: 
Grade 4 
Hold until resolution of toxicity.  G-
CSF administration required.  
Follow reductions in dosing 
schedule and olaparib dosages  as 
per sections  6.6.1 and 6.6.2.  
Hold until resolution of toxicity .  G-
CSF administration required.  
Follow reductions in dosing 
schedule and olaparib dosages  as 
per sections  6.6.1 and 6.6.2.if RP-
3500 dosage already decreased 
for the same toxicity. 
Event Name  
Anemia  
Treat per institutional guidelines including blood transfusions and/or erythropoietins. Consider 
transfusing for symptoms with hemoglobin >8 g/dL (Grade <3) or for any Grade 3 (hemoglobin 
<8 g/dL). If possible, maintain RP-3500 and olaparib doses as long as patient is clinically 
stable, but if a dose reduction or interruption is desired, consult with the Medical Monitor. 
Event  
Hyperkalemia (including rapidly rising potassium)
 
Potassium ≥ 0.5 mmol/L 
increase from prior value 
(and ≤ULN) 
 
Hold RP-3500 and olaparib. Recheck potassium, phosphorous, uric 
acid, calcium, and creatinine in 1 hour. 
 
If additional ≥ 0.2 mmol/L increase in potassium, but still ≤ upper 
limit of normal (ULN), manage per potassium > ULN. 
o If   < 0.2 mmol/L increase in potassium and potassium ≤ ULN 
and no other evidence of tumor lysis, resume camonsertib 
(RP-3500) and olaparib per protocol.. 
Potassium > ULN but < 6 
mmol/L (6.0mEq/L) and 
asymptomatic (e.g. muscle 
cramps, weakness, 
 
Hold camonsertib (RP-3500) and olaparib until resolution to ≤ ULN. 
 
Perform ECG; administer calcium gluconate 100-200 mg/kg IV 
slowly if there is evidence of life-threatening arrhythmias 
o Administer Kayexalate/Resonium 60g if available 
o Administer furosemide 20mg 


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paresthesias, nausea, 
vomiting, and diarrhea) 
o Recheck potassium, phosphorous, uric acid, calcium and 
creatinine in 1 hour after administration of calcium gluconate, 
keyexalate/resonium, furosemide and ECG. If potassium 
≤ULN 1 hour later, repeat potassium, phosphorous, uric acid, 
calcium, and creatinine 1, 2, and 4 hours later, if no other 
evidence of tumor lysis. 
Potassium ≥ 6 mmol/L 
(6.0mEq/L) and 
symptomatic (e.g. muscle 
cramps, weakness, 
paresthesias, nausea, 
vomiting, and diarrhea) 
 
Hold camonsertib (RP-3500) and olaparib until resolution to ≤ ULN. 
 
Perform ECG; administer calcium gluconate 100-200 mg/kg IV 
slowly if there is evidence of life-threatening arrhythmias 
o Administer Kayexalate/Resonium 60g if available 
o Administer furosemide 20mg IV 
o Administer insulin 0.1 U/kg IV + D52 2 mL/kg IV 
o Administer sodium bicarbonate 1 to 2 mEq/kg IV. 
Rasburicase should not also be used as this may exacerbate 
calcium phosphate precipitation. 
o Recheck potassium, phosphorous, uric acid, calcium and 
creatinine every hour.   
Event 
Hyperuricemia  
Uric acid ≥ 8.0 mg/dL (476 
µmol/L) 
 
Hold camonsertib (RP-3500) and olaparib until resolution to < 8.0 
mg/dL (476 μmol/L) 
 
Give rasburicase (as per local guidelines). Sodium bicarbonate 
should not be used as this may exacerbate calcium phosphate 
precipitation. 
 
Recheck potassium, phosphorous, uric acid, calcium, and creatinine 
in 1 hour after rasburicase administration. 
Uric acid ≥ 10 mg/dL (595  
μmol/L) OR Uric acid ≥ 8.0 
mg/dL (476  μmol/L) with 
25% increase and  
creatinine increase ≥ 0.3 
mg/dL (≥ 0.027 mmol/L) 
from predose level. 
 
Hold camonsertib (RP-3500) and olaparib until resolution 
 
Give rasburicase (as per local guidelines). Sodium bicarbonate 
should not be used as this may exacerbate calcium phosphate 
precipitation. 
 
Recheck potassium, phosphorous, uric acid, calcium, and creatinine 
in 1 hour after rasburicase administration. 
 
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorous, 
uric acid, calcium, and creatinine 2 and 4 hours later, if no other 
evidence of tumor lysis. 
Event  
Hypocalcemia  
Corrected calcium ≤ 7.0 
mg/dL (1.75 mmol/L) OR 
Patient symptomatic (e.g., 
muscle cramps, 
 
Hold camonsertib (RP-3500) and olaparib until resolution of calcium 
to > 7.0 mg/dL (1.75 mmol/L) or resolution of symptoms related to 
hypocalcemia. 


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For blood chemistry changes or symptoms suggestive of TLS outside of cycle 1: 
 
Withhold the next day’s dose of RP-3500 and olaparib.  If it resolves within 48 hours of 
last dose resume at the same dose and then proceed with planned therapy. 
 
For any blood chemistry changes requiring > 48 hours to resolve and TLS attributable to 
RP-3500 and olaparib treatment, resume both drugs at one DL lower. 
 
For any events of clinical TLS and attributable to RP-3500 and olaparib treatment, hold 
both drugs and provide best supportive care. When resolved, resume both drugs at one 
DL lower. 
If TLS does not re-occur after 2 weeks of treatment at the reduced doses, increase of both drugs 
to the prior DL can be considered. Should laboratory or clinical TLS re-occur after re-escalation 
to the higher DL, and is attributable to RP-3500 and olaparib treatment, both drugs should be 
permanently lowered to one DL lower. 
6.6.5 Non-hematologic Toxicities 
Specific guidelines are provided below for selected non-hematologic toxicities. In AEs that have 
guidelines for both RP-3500 and olaparib, follow the guideline for the most likely causative agent. 
If the causative agent cannot be determined, hold both RP-3500 and olaparib and follow the 
guidelines for both drugs. 
 
If a patient experiences several adverse events, and there are conflicting recommendations, the 
investigator should use the recommended dose adjustment that reduces the dose to the lowest 
level. Treatment delays for adverse events exceeding 21 days will lead to protocol removal. If 
reduction of the drug doses resolves the patient’s toxicity to grade ≤1 for at least 3 weeks, 
hypotension, tetany, 
cardiac arrhythmias) in the 
presence of hypocalcemia 
 
Administer calcium gluconate 50 to 100 mg/kg IV slowly with ECG 
monitoring unless hyperphosphatemia in which case should address 
in consultation with nephrology. 
 
Recheck potassium, phosphorous, uric acid, calcium, and creatinine 
in 1 hour after administration of calcium gluconate. If calcium 
normalizes 1 hour later, repeat potassium phosphorous, uric acid, 
calcium, and creatinine 2 and 4 hours later, if no other evidence of 
tumor lysis. 
Event  
Hyperphosphatemia  
Phosphate ≥ 0.5 mg/dL 
(1.615 mmol/L) with ≥ 5.0 
mg/dL (0.16 mmol/L) 
increase 
 
Hold camonsertib (RP-3500) and olaparib until resolution to < 5.0 
mg/dL (1.615 mmol/L). 
 
Administer a phosphate binder (e.g., aluminium) 
 
Recheck potassium, phosphorous, uric acid, calcium, and creatinine 
in 1 hour after administration of phosphate binder. If calcium 
normalizes 1 hour later, repeat potassium phosphorous, uric acid, 
calcium, and creatinine 2 and 4 hours later, if no other evidence of 
tumor lysis. 


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increasing RP-3500 and/or olaparib back to the prior dose is permitted. No dose below dose level 
1 (Table 11) for either drug is allowed and should protocol dictate another dose reduction below 
dose level 1, the patient will be removed from study. 
 
Table 14. Management and dose modification guidelines for non-hematologic toxicities 
encountered with combination RP-3500 and olaparib. 
Event 
Name 
Nausea  
Grade of 
Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for Olaparib  
≤ Grade 1 
No change in dose 
5-HT3-antagonists, D2-antagonists or NK1 
antagonists, and benzodiazepines 
administration can prevent or treat nausea 
in the majority of patients.  Consider 
additional anti-emetics as per the NCCN 
Clinical Practice Guideline for 
antiemesis57. Advise patient to take one or 
more anti-nausea medications 30-60min 
prior to taking olaparib. 
Grade 2 
No change in dose. Modify dosing 
schedule of RP-3500 concurrently 
with olaparib. 
Implement one or more combinations of 
anti-nausea medications including 
dexamethasone pre-medication given 30-
60 min prior to taking RP-3500 and 
olaparib. Consider additional anti-emetics 
as per the NCCN Clinical Practice 
Guideline for antiemesis57.  Advise patient 
to take one or more anti-nausea 
medications 30-60min prior to taking 
olaparib. Olanzapine 2.5 to 5mg every 
morning, as per NCCN guidelines, can 
mitigate nausea/vomiting. If nausea 
persists at grade 2 for ≥7 days, hold 
olaparib. May resume olaparib at the same 
dose if nausea becomes ≤ grade 1. If 
grade 2 nausea reoccurs for ≥7 days for a 
second occurrence despite maximal 
supportive care, then follow reductions in 
dosing schedule and drug dosages as per 
sections  6.6.1 and 6.6.2. If patient’s 
nausea is grade ≤1 for 3 weeks, then the 
dose or dosing schedule of olaparib may 


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be increased back to the previous 
dose/schedule. 
Grade 3 
No change in dose.  Modify dosing 
schedule of RP-3500 concurrently 
with olaparib. 
Hold drug and implement one or more 
combinations of anti-nausea medications 
including dexamethasone pre-medication 
given 30-60 min prior to taking RP-3500 
and olaparib.  Consider additional anti-
emetics as per the NCCN Clinical Practice 
Guideline for antiemesis57.  May restart 
olaparib at the same dose level once 
nausea becomes ≤ grade 1 and advise the 
patient to take one or more anti-nausea 
medications 30-60min prior to taking 
olaparib. Olanzapine 2.5 to 5mg every 
morning, as per NCCN guidelines, can 
mitigate nausea/vomiting. If grade 3 
nausea reoccurs, hold drug until nausea 
resolves to ≤ grade 1 and resume olaparib 
with a dose reduction following reductions 
in dosing schedule and drug dosages as 
per sections 6.6.1 and 6.6.2. If patient’s 
nausea is grade ≤1 for 3 weeks at the 
reduced dose/schedule, then olaparib may 
be increased back to the previous 
dose/schedule. 
Event 
Name 
Vomiting  
Grade of 
Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for Olaparib  
≤ Grade 2 
No change in dose 
No change in dose.   Implement one or 
more combinations of anti-nausea 
medications including dexamethasone 
pre-medication given 30-60 min prior to 
taking RP-3500 and olaparib.  Consider 
additional anti-emetics as per the NCCN 
Clinical Practice Guideline for 
antiemesis57.   Advise patient to take one 
or more anti-nausea medications 30-
60min prior to taking olaparib. Olanzapine 
2.5 to 5mg every morning, as per NCCN 
guidelines, can mitigate nausea/vomiting. 


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Grade 3 
No change in dose. Modify dosing 
schedule of RP-3500 concurrently 
with olaparib. 
Hold until toxicity ≤ grade 1 and resume 
treatment with reduction of dosing 
following reductions in dosing schedule 
and drug dosages as per sections  6.6.1 
and 6.6.2.  Implement maximal supportive 
care measures including dexamethasone 
pre-medication 30-60 min prior to taking 
RP-3500 and olaparib. Olanzapine 2.5 to 
5mg every morning, as per NCCN 
guidelines, can mitigate nausea/vomiting. 
If patient’s vomiting is grade ≤1 for 3 
weeks at the reduced dose/schedule, then 
olaparib may be increased back to the 
previous dose/schedule. 
Event 
Name 
Diarrhea  
Grade of 
Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for Olaparib  
≤ Grade 1 
No change in dose 
Rule out other causes of diarrhea, 
including infectious etiologies and drug 
effects.  At the first sign of loose or 
abnormal stool, it is recommended that the 
patient be treated according to institutional 
standard of care.  Maintain dose of 
olaparib. 
Grade 2 
No change in dose.  Modify dosing 
schedule of RP-3500 concurrently 
with olaparib. 
If diarrhea is present despite maximal anti-
diarrheal medications, rule out other 
causes of diarrhea, including infectious 
etiologies and drug effects.  Reduce 
olaparib following reductions in dosing 
schedule and drug dosages as per 
sections  6.6.1 and 6.6.2(i.e. dosing 
schedule with either sequential or 
concurrent decrease in olaparib dose 
level) until resolved to grade ≤1, then 
increase olaparib to prior dose and/or 
schedule.  If toxicity recurs at grade ≥2, 
then reduce olaparib following reductions 
in dosing schedule and drug dosages as 
per sections  6.6.1 and 6.6.2.  If patient is 
stable and diarrhea resolves (grade 0 or 


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baseline) for 3 weeks, olaparib may be re-
escalated to prior dose/schedule. 
≥ Grade 3 
No change in dose.  Modify dosing 
schedule of RP-3500 concurrently 
with olaparib. 
If diarrhea is present despite maximal anti-
diarrheal medications, rule out other 
causes of diarrhea, including infectious 
etiologies and drug effects.  Hold olaparib 
until toxicity is grade ≤1, then restart 
olaparib following reductions in dosing 
schedule and drug dosages as per 
sections  6.6.1 and 6.6.2 (i.e. dosing 
schedule with either sequential or 
concurrent decrease in olaparib dose 
level).  If patient is stable and diarrhea 
resolves (grade 0 or baseline) for 3 weeks, 
olaparib may be re-escalated to prior 
dose/schedule. 
Event 
Name 
Fatigue  
Grade of 
Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for Olaparib  
Grade 1 
Maintain dose. Rule out other causes. 
If found to be anemic and 
symptomatic, consider transfusing 
even with hemoglobin >8g/dL. 
Consider adding dexamethasone 4-
8mg pre-medication on days of RP-
3500/olaparib administration. 
Maintain dose. Rule out other causes. If 
found to be anemic and symptomatic, 
consider transfusing even with hemoglobin 
>8g/dL. Consider adding dexamethasone 
4-8mg pre-medication on days of RP-
3500/olaparib administration. 
Grade 2 
lasting ≤7 
days 
As per NCCN guidelines, consider 
stimulants such as methylphenidate 
5mg QD in the morning only. 
Consider adding dexamethasone 4-
8mg pre-medication on days of RP-
3500/olaparib administration. 
As per NCCN guidelines, consider 
stimulants such as methylphenidate 5mg 
QD in the morning only. Consider adding 
dexamethasone 4-8mg pre-medication on 
days of RP-3500/olaparib administration. 
Grade 2 
lasting >7 
days or 
grade ≥3 
Rule out other causes. If found to be 
anemic and symptomatic, consider 
transfusing even for hemoglobin >8 
g/dL. As per NCCN guidelines, 
consider stimulants such as 
methylphenidate 5mg QD in the 
morning only. Hold RP-3500 dosing 
until resolved to ≤ grade 1 or 
Rule out other causes. If found to be 
anemic and symptomatic, consider 
Transfusing even for hemoglobin >8 g/dL. 
As per NCCN guidelines, consider 
stimulants such as methylphenidate 5mg 
QD in the morning only. Hold olaparib 
dosing until resolved to ≤ grade 1 or 
baseline. For first occurrence, restart 


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baseline. For first occurrence, restart 
RP-3500 at current dose and 
schedule. For second occurrence, 
reduce RP-3500 and olaparib 
treatments following reductions in 
dosing schedule and drug dosages 
as per sections 6.6.1 and 6.6.2.  
Consider adding dexamethasone 4-
8mg pre-medication on days of RP-
3500/olaparib administration. If 
patient is stable and fatigue resolves 
(≤ grade 1 or baseline) for 3 weeks, 
RP-3500 may be re-escalated to prior 
dose. 
olaparib at current dose and schedule. For 
second occurrence, reduce olaparib and 
RP-3500 treatment following reductions in 
dosing schedule and drug dosages as per 
sections 6.6.1 and 6.6.2. Consider adding 
dexamethasone 4-8mg pre-medication on 
days of RP-3500/olaparib administration. If 
patient is stable and fatigue resolves (≤ 
grade 1 or baseline) for 3 weeks, olaparib 
may be re-escalated to prior dose. 
Event 
Name 
Dyspnea  
Grade of 
Event  
Management/Next Dose for RP -
3500 
Management/Next Dose for Olaparib  
Grade 1 
No change in dose 
Rule out other causes, including infection, 
primary pulmonary causes (i.e. embolism, 
effusion and edema), cardiac etiologies 
and drug effects. Consider transfusing 
even if patient’s hemoglobin is >8g/dL. 
Maintain dose. 
≥ Grade 2 
No change in dose.  Modify dosing 
schedule of RP-3500 concurrently 
with olaparib. 
Rule out other causes, including infection, 
primary pulmonary causes (i.e. embolism, 
effusion and edema), cardiac etiologies 
and drug effects. Consider transfusing 
even if patient’s hemoglobin is >8g/dL. 
Hold olaparib until toxicity resolves to 
grade ≤1. Resume olaparib at the same 
dose and schedule. If toxicity reoccurs 
despite maximal supportive care or 
treatment of underlying cause, reduce 
olaparib and RP-3500 following reductions 
in dosing schedule and drug dosages as 
per sections 6.6.1 and 6.6.2.  If patient’s 
dyspnea is grade ≤1 for 3 weeks at the 
reduced dose, then olaparib may be 
increased back to the previous 
dose/schedule. 
Other Non-Hematologic Toxicity
 
≥ Grade 3 
Hold the causative agent until toxicity is ≤ grade 1 or baseline.   
Implement maximal supportive care and rule out other potential causes of that 
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6.7 
Concomitant Medications and Therapies  
All administered concomitant medications (including herbal supplements) and non-medicinal 
therapies (including transfusions) used 28 days prior to Cycle One Day One, and until 30 days 
after the last dose of study therapy will be recorded in the subject’s research chart and 
corresponding eCRF. All medications, including those used to treat adverse events, chronic 
conditions or diseases, or as supportive therapy should be documented in the eCRF.  
6.7.1 Prohibited Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the active treatment period (Refer to Appendix 5). Subjects are prohibited from receiving the 
following therapies during the treatment phase of this trial:  
 
Anti-cancer systemic chemotherapy or biological therapy;  
 
Other investigational agents;  
o Exception: therapies given for the prevention, treatment or management of 
COVID-19 under the FDA emergency use authorization are allowed. 
 
Radiation therapy >10 Gy to any one lesion; 
 
Any live-attenuated vaccine therapies for the prevention of infectious disease (e.g. MMR, 
or rotavirus); 
o Exception: Vaccines for the prevention of COVID-19 are allowed. 
 
Herbal remedies known to potentially interfere with major organ function (e.g. hypericin);  
 
Strong P-glycoprotein inhibitors (P-gp); 
 
Breast Cancer Resistance Protein (BCRP) inhibitors; 
 
Strong CYP3A4 inhibitors and/or inducers. 
If a subject requires treatment with one or more of the listed prohibited medications, the subject 
may need to be taken off study therapy. Each case will be considered and if possible, the 
investigator should discuss with the DSMC and Medical Monitor prior to initiating prohibited 
therapy. 
6.8 
Recommended Infectious Prophylaxis
 
The use of infectious prophylaxis medications are strongly recommended given the 
immunocompromised state of CLL patients and potential for leukopenia/neutropenia while being 
treated with RP-3500 and olaparib. While prophylaxis regimens can be determined by the treating 
upon investigator discussions. If treatment delay is >7 days but ≤21 days, restart 
treatments following reductions in dosing schedule and drug dosages as per 
sections 6.6.1 and 6.6.2 in which changes in dosing schedule of both drugs 
should first be implemented with either sequential or concurrent reductions in drug 
dosages. If treatment delay >21 days, discontinue study.   


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provider and according to institutional guidelines, Table 15 summarizes the recommended 
regimens for infectious prophylaxis and appropriate alternatives. If the patient is allergic to all of 
the medications listed for each specific type of infection, then an infectious disease physician 
should be consulted for help in management. 
G-CSF administration and formulation are as per institutional standard. 
Table 15. Recommended infection prophylaxis medications. 
Prophylaxis  
Preferred Medication 
Alternative Medication 
Duration 
Viral  
 Herpes Simplex 
 Varicella Zoster 
 
Acyclovir* 400mg to 
800mg PO BID 
 
Valacyclovir* 500mg 
to 1000mg PO daily 
 
Entirety of treatment 
and trial 
Bacterial (if 
neutropenia with 
ANC <1,000/µL is 
expected to last ≥7 
days) 
 G-CSF 
administration is 
strongly 
recommended 
 Levofloxacin* 
500mg PO/IV daily 
 G-CSF 
administration is 
strongly 
recommended 
 Cefpoxodime* 
200mg PO BID or, 
 Ciprofloxacin* 
500mg PO BID 
Until ANC >500/µL 
for 3 consecutive 
days 
Immunoglobulin 
replacement  
therapy  
Hypogammaglobulinemia is common in CLL patients. Replacement 
with IVIG may be indicated for patients with IgG levels <500 and 
recurrent infections. However, some patients may benefit from IVIG 
replacement even if IgG is ≥500 if recurrent infections were common 
in their prior clinical history.  
*Adjust for renal function 
 
6.9 
Duration of Therapy  
Subjects will receive combined treatment until treatment discontinuation criteria is met. Upon 
meeting treatment discontinuation criteria, subjects will continue on the study in follow-up until 
study discontinuation criteria are met.  
6.9.1 Criteria for the Discontinuation of Treatment 
Subjects may withdraw from treatment or the study overall at any time at their request, or they 
may be withdrawn at the discretion of the Investigator or Sponsor for safety, behavioral reasons, 
or the inability of the subject to comply with the protocol-required schedule of study visits or 
procedures. In addition to the drug-specific discontinuation criteria listed in section 7, the following 
will result in treatment discontinuation: 
 
The subject requests to discontinue the study treatment and/or study procedures;  


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 
Clinical deterioration that, in the opinion of the investigator, increases the risk to the 
subject; 
 
Confirmed disease progression based on iwCLL 2018 criteria (Section 7.5.3);  
 
Adverse events or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from study treatment; 
 
Significant noncompliance with the protocol schedule or treatment administration in the 
opinion of the investigator; 
 
Pregnancy; 
6.9.2 Criteria for the Discontinuation of Study  
Subjects will be taken off study for the following: 
 
Completed study follow-up period; 
 
Participant or legally authorized representative requests to be fully withdrawn from the 
study;  
 
If, in the investigator's opinion, the continuation of the trial would be harmful to the subject's 
well-being; 
 
The subject is lost to follow-up;  
 
Screen failure; 
 
Death. 
6.9.3 Withdrawal of consent 
Subjects are free to withdraw from the study at any time without prejudice to further treatment. 
Subjects who withdraw consent for further participation in the study will not receive any further 
study medications or further study observation.  
If a subject withdraws consent, they will be specifically asked if they are withdrawing consent to 
all further participation in the study including any further follow-up (e.g., survival contact telephone 
calls). Survival status may be obtained from public records for subjects who have withdrawn from 
any further follow-up contact. 
6.9.4 Long Term Follow-Up for OS 
Subjects that discontinue study treatment for any reason other than disease progression, must 
continue to have disease assessments until disease progression or the initiation of subsequent 
anticancer therapy per Section 4.5. 
Upon discontinuation of study therapy, subjects will be followed for OS for 10 years from the date 
of study therapy initiation. Subjects or their legally authorized representatives will be contacted 
every 6 months (±14 days) during the first 5 years and then yearly (±28 days) during the following 
years thereafter until death, end of the study, or subject withdrawal of consent, whichever comes 
first. Survival and subsequent treatment status may be collected by public records, medical 


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records, or by contacting the subject or their legally authorized representative by phone. All efforts 
should be made to contact the subject at these time points. Refer below for Lost to Follow-Up 
guidelines. 
6.9.4.1 Lost to Follow-Up 
Subjects will be considered lost to follow-up only if no contact has been established by the time 
the study is completed, such that there is insufficient information to determine the subject’s status 
at that time. Subjects who refuse to continue participation in the study, including telephone 
contact, should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing subjects throughout 
the study period. If contact with a missing subject is re-established, the subject should not be 
considered lost to follow-up and evaluations should resume according to the protocol. 
When a subject is lost to follow-up, site personnel should check hospital records, the subjects’ 
current physician, and a publicly available death registry to obtain a current survival status.  
In the event that the subject has actively withdrawn consent, the survival status of the subject can 
be obtained by site personnel from publicly available death. 
7 
STUDY ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that there may be circumstances, outside of 
the control of the Investigator that may make it unfeasible to perform the test. In these cases, the 
Investigator will take all steps necessary to ensure the safety and well-being of the subject. When 
a protocol-required test cannot be performed, the Investigator will document the reason for this 
and any corrective and preventive actions that he or she has taken to ensure that normal 
processes are adhered to as soon as possible. 
7.1 
General  Assessments  
7.1.1 Participant Consent 
Before the initiation of any study procedures, all potential subjects or their legal representative 
must be fully informed of the risks and potential benefits of trial participation and demonstrate 
understanding. An informed consent document must be signed and dated by the participant or 
their legal representative indicating that they understand the risks and consent to participation 
and treatment on the study. The Principal Investigator or their appropriately trained and delegated 
study personnel conducting the informed consent discussion must also sign and date the 
document. A copy of the signed document should be provided to the subject. 
Procedures, laboratory tests, or imaging performed as part of the standard of care prior to subject 
consent may contribute to the assessment of eligibility and/or screening procedures if performed 
during the screening period.  
7.1.2 Medical History 
The investigator or appropriately trained and delegated study personnel will collect medical history 
to the extent that supports the assessment of eligibility. The medical history will include any active 


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conditions and any conditions deemed to be clinically significant by the treating investigator. The 
use of symptom terms should be discouraged; if possible, terms describing the principal condition 
or syndrome should be used.  
When collecting the initial medical history at screening, specific attention should be given to: 
 
Baseline symptoms 
 
A detailed history of prior cancers and cancer therapies including start and stop dates 
(duration of therapy), disease progression during or after therapy, discontinuation of 
therapies due to intolerability or any other serious illness, and length of remission. 
 
Past surgical, family, and social histories 
 
Past medical history as well as currently managed medical problems and their treatments 
 
ECOG performance status 
When collecting medical history at subsequent study visits, specific attention should be given to: 
 
New symptoms related to potential adverse events 
 
Status of disease 
 
Management of previously documented adverse events and their current grade 
7.1.3 Cancer History 
The oncologic history of the patient’s CLL will be collected at the screening visit and will include: 
 
CLL status at initial diagnosis (if known) 
o Date of diagnosis 
o Age at diagnosis 
o Relevant laboratory measures including but not limited to complete blood count 
with differential, CLL FISH, beta 2 microglobulin, CLL NGS, IGHV mutational 
status, karyotype, CLL flow cytometry markers. 
o Rai and Binet stages 
o Presence of B-symptoms 
 
Time to first treatment – defined as days from date of initial diagnosis to date of first 
treatment initiation 
 
Prior treatment regimens 
o Treatment name and type 
o Duration of therapy (if available, start and stop dates) 
o Best response on therapy 
o Reason for discontinuation 
o Sequence of therapies 
o Toxicities encountered while on each treatment regimen 
o Length of remission 


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 
Current indication for treatment 
7.1.4 Concomitant Medications 
All medications currently being used by a study participant, regularly or as needed, must be 
reviewed and documented by the investigator or qualified designee. Specific attention should be 
given to medications with a protocol required washout as described in the exclusion criteria and 
any medication taken 28 days prior to cycle one day one. Refer to Section 6.7 for prohibited 
medications.  
During protocol therapy, any medications taken by the patient or used to treat an adverse event 
will be documented in the subject’s research chart and the corresponding eCRF. If a new 
anticancer therapy is initiated during study follow-up, the new therapy should also be recorded in 
the subject’s research chart and corresponding eCRF.  
7.1.5 CLL FISH Testing 
It is required that all subjects have CLL FISH analysis after progression is noted from the most 
recent line of therapy and within 6 months of screening. Testing will be accepted from either 
peripheral blood and/or bone marrow samples. FISH probes should be directed to detect 
deletion 13q14, trisomy 12, deletion 11q22.3, and deletion 17p13. The CLL FISH testing must 
be confirmed by a Clinical Laboratory Improvement Amendments (CLIA) approved test. All FISH 
abnormalities should be recorded along with whether the deletion 13q14 was monoallelic or 
biallelic. If a patient has multiple FISH abnormalities, hierarchal FISH should be used9. 
7.1.6 Mutation Testing 
It is required that all subjects have documentation of the necessary somatic mutations through 
local laboratory testing. Somatic mutation testing must be performed after progression is noted 
from the most recent line of therapy and within 6 months of screening. Testing will be accepted 
from either peripheral blood and/or bone marrow samples. At a minimum, the following somatic 
mutations should be tested: TP53, ATM, SF3B1, POT1, and XPO1. While not required, the 
following genes are strongly encouraged to be tested: NOTCH1, BIRC3, BRAF, KRAS, DDX3X, 
MYD88, and CXCR4. All detected gene mutations and their respective variant allele frequency 
(VAF) percentage should be recorded. The mutational status must be confirmed by a CLIA 
approved test.  
7.2 
Safety Assessments  
7.2.1 Physical Examinations and Vital Signs 
Subjects will have physical examinations to include major body systems, vital signs (blood 
pressure, heart rate, respiration rate, pulse oximetry, and body temperature), assessment of 
ECOG performance status (see Appendix 1), weight, and height at the time points described in 
the Schedule of Events. Particular attention should be paid to lymph nodes, spleen and liver. 
Documentation of lymph nodes should include location(s) and size (in centimeters) as noted in 
two orthogonal directions. Liver size should be documented as enlargement of the liver below the 
costavertebral angle as measured from the right mid-supraclavicular line in centimeters. Spleen 


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size should be documented as enlargement of the spleen below the costaverteral angle as 
measured from the left mid-supraclavicular line in centimeters. 
7.2.2 Adverse Events 
Adverse events experienced during trial participation will be collected per the Schedule of Events 
and Adverse Events Section. Each study participant will be questioned about the occurrence of 
adverse events in a non-leading manner. Should the treating investigator feel that the adverse 
event is attributed to study therapy, dose modification guidelines in the Dose Modification Section 
will be followed.  
7.2.3 Laboratory Assessments 
Samples for all laboratory assessments will be drawn at the time points indicated in the Schedule 
of Events and when clinically indicated. All safety laboratory analyses will be performed by the 
local laboratory for each study center. When applicable, all safety laboratory assessments must 
be reviewed by the treating investigator before study drug administration. When applicable, 
results from the pregnancy test must also be available for review before dosing.  
Table 16: Laboratory Assessments
 
Laboratory Assessments
 
Complete Blood Count with 
Platelet Count and 
Differential  
 
White Blood Cell Count 
 
Hemoglobin 
 
Platelets 
 
Manual or automated white blood cell count 
differential including: 
o Absolute Neutrophil Count 
o Absolute Lymphocytes 
 Chemistry  
 
Complete Metabolic Panel 
o Sodium 
o Potassium 
o Chloride 
o Carbon Dioxide 
o Alkaline Phosphatase 
o Aspartate Aminotransferase 
o Alanine Aminotransferase 
o Urea Nitrogen 
o Glucose 
o Creatinine 
o Calcium 
o Protein 
o Albumin 
o Total Bilirubin 
Tumor Lysis Syndrome 
(TLS) 
 Lactate dehydrogenase 
 Phosphorus 
 
Uric acid 


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Urine  
 
24 hour urine 
HIV and Hepatitis Serologies
 
 
Hepatitis B Virus (HBV): 
o Hepatitis B surface antigen (HBsAg) 
o Antibody to hepatitis B core antigen (anti-HBc) 
o Antibody to hepatitis B surface antigen (anti-
HBs) 
o HBV DNA quantification (for subjects who are 
anti-HBs positive) 
 
Hepatitis C Virus (HCV): 
o Antibody to Hepatitis C (anti-HCV) 
o HCV-RNA (for subjects who are anti-HCV 
positive) 
 
HIV 
o Human Immunodeficiency Virus (HIV) Combo 
Antigen/Antibody (HIV-1/O/2) 
Pregnancy  
 
Beta-hCG Qualitative Urine or Serum 
 
7.3 
12-Lead Electrocardiograms
  
Standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs. All subjects 
will require triplicate 12-lead ECG measurement with tracings approximately one-minute apart 
which will be performed according to the Schedule of Events. The parameters to be recorded 
are QT, QTc, PR, and QRS. All ECGs should be conducted pre-dose and Fridericia's formula 
will be used for all QT correction calculations. The mean QTcF from these ECGs should be 
recorded.   
 
7.4 
Efficacy Assessments
 
7.4.1 Disease Assessment 
Disease assessments will include complete blood count with differential, CT scans of the neck, 
chest, abdomen, and pelvis, peripheral blood immunophenotyping, and bone marrow biopsy and 
aspirate at the time points indicated on the Schedule of Events. 
7.4.2 Disease Assessment Algorithm 
All patients should have a CT scan of the neck, chest, abdomen, and pelvis with IV contrast at 
the time of screening or up to 28 days prior to C1D1. CTs are required at C4D1 (± 7 days). 
Should this CT show that the patient has achieved an iwCLL 2018 defined complete remission 
(CR) and absolute lymphocyte count is <4000, then a bone marrow biopsy should be performed 
to confirm CR. 
At any other study time point beyond C4D1 excluding end of treatment, the patient may have a 
disease assessment if the subject achieves hematologic recovery or the treating physician 
suspects the patient has achieved a CR as per the 2018 iwCLL criteria. At that time, a 
peripheral blood immunophenotype should be ordered. If the peripheral blood 


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immunophenotype shows no evidence of circulating CLL cells, then CTs of the neck, chest, 
abdomen, and pelvis should be performed. Should the CT also confirm CR, then a bone marrow 
biopsy should be performed to confirm CR. The study team has 28 days to complete all 
necessary testing required to confirm a CR from the time a CR is suspected by the treating 
physician. During this time, protocol treatment may continue as prescribed. 
7.4.3 End of Treatment Assessment 
Patients who come off study for any reason should have an end of treatment assessment as 
outlined in the Schedule of Events. 
7.4.4 Patients with Iodine Contrast Allergy 
If a patient has a history of an allergy to iodine contrast as required by the CTs, then 
premedications should be offered to the patient. Premedications can follow institutional 
guidelines or the offered schedule below: 
 
13 hours prior to CT: 50 mg PO prednisone 
 
7 hours prior to CT: 50 mg PO prednisone 
 
1 hour prior to CT: 50 mg PO prednisone and 50 mg PO Benadryl 
If a patient refuses iodine contrast allergy even when premedications are offered, then CTs may 
be performed without iodine contrast. 
7.4.5 Peripheral Blood Immunophenotyping 
Peripheral blood immunophenotyping are required at screening and to confirm a CR as outlined 
on the Schedule of Events. This is a flow cytometry based test to confirm markers present on 
CLL cells.  These markers include but are not limited to CD5, CD10, CD19, CD20, CD23, 
CD200 and kappa/lambda light chain restriction. The percentage of CLL cells that make up the 
total population of leukocytes should be recorded. The peripheral blood immunophenotyping 
must be confirmed by a CLIA approved test. 
7.4.6 Bone Marrow Biopsy 
At a minimum, marrow core and aspirate testing should include pathological review of the core 
sample, leukocyte and lymphocyte flow cytometry and minimal residual disease testing by flow 
cytometry (as per institutional standard). Other testing is at the discretion of the treating provider. 
The CLL FISH and CLL NGS required at the time of screening may be performed on either 
peripheral blood or bone marrow biopsy as long as the test produces a successful result. If the 
presence of lymphoid nodules are noted by the pathologist, immunohistochemistry of these 
nodules should be performed to define whether these are primarily T cells, B cells other than CLL 
cells or CLL cells. The following data points should be recorded in the corresponding eCRF.  
 
Lymphocyte percentage and count 
 
Presence of lymphoid of nodules – If presence is noted, additional immunohistochemistry 
tests should be performed on these nodules to define whether these nodules comprise 
primarily T cells, B cells other than CLL cells or CLL cells 


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 
Percent cellularity  
 
Percent of CLL cells detected on flow cytometry 
 
Percent of CLL cells comprising the entire marrow if detected by morphology and 
immunohistochemistry 
 
CLL MRD by flow cytometry (if performed) 
 
CLL MRD by NGS (if performed and resulted) 
 
Bone marrow fibrosis grade (if performed) 
 
Any NGS identified mutations (if performed) 
 
Cytogenetics (if performed) 
 
CLL FISH (if performed) 
If the patient has had a previous bone marrow biopsy that has demonstrated a CR while on trial, 
a repeat bone marrow biopsy is not required while the subject is still enrolled on trial unless the 
treating provider suspects progression of disease. 
7.5 
Definition  of Response and Progression
 
Disease response assessments will be according to the 2018 iwCLL definitions of response and 
progression. It is summarized in Table 17. 
Table 17. Response definitions and criteria. 
Parameter  
Complete 
remission (CR)*  
Partial 
remission 
(PR)* 
Progressive 
disease ( PD)* 
Stable disease 
(SD)* 
 
All criteria below 
must be met 
At least 2 of the 
parameters of 
group A and 1 
parameter of 
group B must 
improve if 
previously 
abnormal; if 
only 1 
parameter of 
both groups A 
and B is 
abnormal 
before therapy, 
only 1 must 
improve 
At least 1 of the 
criteria of group A 
or group B must be 
met; constitutional 
symptoms alone do 
not define PD 
All of the criteria 
must be met 
Group A   


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Parameter  
Complete 
remission (CR)*  
Partial 
remission 
(PR)* 
Progressive 
disease ( PD)* 
Stable disease 
(SD)* 
Lymph nodes 
None > 1.5 cm 
Decrease ≥ 
50% (from 
baseline)* 
Increase ≥ 50% 
from best response 
Change of -49% to 
+49% from 
baseline 
Liver and/or 
spleen size** 
Spleen size < 13; 
liver size normal 
Decrease ≥ 
50% (from 
baseline) 
Increase ≥ 50% 
from best response 
Change of -49% to 
+49% from 
baseline 
Constitutional 
Symptoms 
None 
Any 
Any 
Any 
Circulating 
lymphocyte count 
Normal 
Decrease ≥ 
50% (from 
baseline) 
Increase  ≥ 50% 
over  baseline  
Change of -49% to 
+49% from 
baseline 
Group B  
Platelet count 
≥ 100,000/mcL 
> 100,000/mcL 
or increase ≥ 
50% over 
baseline 
Decrease of ≥ 50% 
from baseline 
secondary to CLL 
Change of -49% to 
+49% from 
baseline 
Hemoglobin 
≥ 11.0 g/dL 
> 11 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 
Normocellular, no 
CLL cells, no B-
lymnphoid 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 
7.5.1 Complete Remission 
CR requires all of the following criteria: 
 
Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 x 109/L 
(4,000/mm3). 
 
Absence of significant lymphadenopathy (i.e., lymph nodes >1.5 cm in diameter) and 
hepatosplenomegaly by physical examination. 
 
CT scan of the abdomen, pelvis, and thorax should be performed, showing no lymph 
nodes larger than 1.5 cm in diameter and no hepatosplenomegaly with spleen size 
<13cm. 
 
Absence of disease-related constitutional symptoms. 
 
Blood counts above the following values: 


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o Neutrophils ≥1.5 x 109/L (1,500/mm3). 
o Platelets ≥100 x 109/L (100,000/mm3). 
o Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusion. 
 
Bone Marrow Aspirate/Biopsy: 
o For a CR, the cytological or pathological evaluation of the bone marrow smear or 
biopsy must be at least normocellular for age, without evidence for typical CLL 
lymphocytes by morphological criteria. 
o If the marrow is hypocellular, a repeat determination should be performed after 4 
weeks, when peripheral blood counts have recovered. However, this time interval 
should not exceed 6 months after the last treatment. A marrow biopsy should be 
compared with that of pretreatment marrow.  
o The quality of the CR should be assessed for MRD by flow 
 
For patients who fulfill the criteria for a CR, but have a persistent anemia, thrombocytopenia or 
neutropenia apparently unrelated to CLL, but related to drug toxicity, these patients should be 
labeled as a CR with incomplete marrow recovery (CRi). A bone marrow evaluation must be 
performed with scrutiny and not show any clonal disease infiltrate. 
7.5.2 Partial Remission (PR) 
PR is defined by achieving at least 2 of the criteria described in Sections 7.4.1a, 7.4.1b, or 
7.4.1c (if abnormal before therapy), as well as one or more of the features listed in section 7.2d. 
If only 1 parameter in Sections 7.4.1a, 7.4.1b, 7.4.1c, 7.4.1d were abnormal before therapy, only 
1 needs to improve. 
 
A decrease in the number of blood lymphocytes to 50% or less from the value recorded 
immediately prior to initial dose of therapy. 
 
Reduction in lymphadenopathy compared with baseline by palpation as defined by the 
following:  (Additional assessment of response by CT scan of abdomen, pelvis, and 
thorax should be performed per study calendar.): 
o A decrease in lymph node size by 50% or more either in the sum of the longest 
diameters of the enlarged lymph node(s) selected at baseline as assessed by 
physical examination (an established number has been a maximum of 6) or the 
sum products of the same enlarged lymph nodes selected at baseline as 
assessed by imaging (an established number in clinical trials of lymph nodes has 
been up to 6).  
o No increase in any lymph node, and no new enlarged lymph node. In small 
lymph nodes (longest diameter < 1.5 cm), an increase <25% is not considered 
significant.  
 
A regression ≥ 50% of the extent of enlargement of the spleen below the costal margin 
defined by palpation, or normalization in size. When assessed by CT, scan spleen size 


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must have regressed by ≥ 50% in length beyond normal. A persistence of splenomegaly 
posttherapy may have limited influence on outcome in CLL. 
 
A regression of ≥ 50% of the extent of enlargement of the liver below the costal margin 
defined by palpation, or normalization in size. Given the impact of numerous medical 
conditions, liver size by physical examination or CT scan is not a reliable measure of 
hepatic involvement by CLL and should only be counted if hepatomegaly is clearly 
attributable to lymphoid involvement. 
 
The blood count should show one of the following results: 
o Platelet counts greater than 100 × 109/L (100,000/mcL) or 50% improvement 
over baseline. 
o Hemoglobin greater than 110 g/L (11.0 g/dL) or 50% improvement over baseline 
without requiring red blood cell transfusions 
Patients who achieve a CR as per section 7.5.1 but bone marrow examination shows residual 
lymphoid nodules deemed related to CLL residual disease will be labeled as having achieved a 
nodular partial remission (nPR). 
7.5.3 Progressive Disease 
Progressive disease during or after therapy is characterized by at least one of the following: 
 
Lymphadenopathy: Progression of lymphadenopathy as confirmed by physical 
examination. Disease progression occurs if one of the following events is observed: 
o Appearance of any new lesion, such as enlarged lymph nodes (≥ 1.5 cm), 
splenomegaly, hepatomegaly, or other organ infiltrates. 
o An increase by 50% or more in greatest determined diameter of any previous 
site. 
 
Splenomegaly:  An increase in the spleen size by ≥ 50% of the extent of enlargement of 
the spleen below the costal margin or the de novo appearance of splenomegaly defined 
by palpation. If no prior splenomegaly was observed at baseline or if splenomegaly has 
resolved with treatment, the spleen must increase by at least 2 cm from baseline.  
 
An increase in the liver size of ≥ 50% of the extent enlargement of the liver below the 
costal margin defined by palpation, or the de novo appearance of hepatomegaly. Given 
the impact of numerous medical conditions, liver size by physical examination or by CT 
scan is not a reliable measure of hepatic involvement by CLL and should only be 
counted if hepatomegaly is clearly attributable to lymphoid involvement. 
 
An increase in the number of blood lymphocytes by 50% or more with at least 5 x 109/L 
B lymphocytes. 
 
Transformation to a more aggressive histology (e.g., Richter syndrome or Richter 
transformation). Whenever possible, this diagnosis should be established by lymph node 
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 
Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) directly attributable 
to CLL and unrelated to autoimmune cytopenias. 
o During Therapy: Cytopenias may occur as a side effect of many therapies and 
should be assessed according to CTCAE criteria. During therapy, cytopenias 
cannot be used to define disease progression. Dose reductions for cytopenias 
are outlined in Section 6. 
o After Treatment: The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of Hb levels by ≥ 20 g/L (2 g/dL) or < 
100 g/L (10 g/dL), or by a decrease of platelet counts by ≥ 50% or to < 100 x 
109/L, which occurs at least 3 months after treatment, defines disease 
progression, if the marrow biopsy demonstrates an infiltrate of clonal CLL cells 
and is not considered treatment-related toxicity. 
7.5.4 Stable Disease 
Patients who have not achieved a CR, or PR and who have not exhibited progressive disease, 
will be considered to have stable disease (which is equivalent to a nonresponse). 
7.6 
Correlative  Studies  
To support exploratory objectives and correlative studies, blood and bone marrow aspirate will be 
collected at the time points indicated on the Schedule of Events. After completion of the described 
correlative studies, any remaining blood or bone marrow aspirate will be stored for future 
unspecified cancer research. With the participant’s approval and as approved by the Institutional 
Review Board (IRB), de-identified biological samples will be stored at Huntsman Cancer Institute’s  
Biorepository.  
At the time of consent, subjects will be given the opportunity to authorize the biobanking of their 
remaining samples for use in future undisclosed research. During the conduct of the study, an 
individual participant can choose to withdraw consent to have biological specimens stored for 
future research. However, the withdrawal of consent with regard to biosample storage may not 
be possible after the study is completed. 
7.6.1 Peripheral Blood Samples For Correlatives 
Up to 40mLof blood will be collected at the time points listed in the Schedule of Events. See the 
lab manual for collection, processing, and storage instructions. 
7.6.1.1 Measurement of DNA Damage and Repair Markers 
The peripheral blood specimens will be assessed for DNA damage by quantitation of γH2AX 
and cleaved PARP1 in CD5+/CD19+ cells by flow cytometry. The sample obtained prior to drug 
administration on C1D1 for each patient will serve as the baseline for that patient and follow-up 
samples will be compared back to that baseline. We will calculate the change from baseline for 
each patient and aggregate the data for all patients to look for common outcomes. 


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7.6.1.2 Apoptosis Markers 
Apoptosis will be assessed at the time points listed on the Schedule of Events. See the lab 
manual or correlative specimen for collection, processing and storage instructions.   
7.6.1.3 Minimal Residual Disease 
At any time point in which a MRD specimen is required from the peripheral blood as according 
to the Schedule of Events two samples should be collected.  One sample will be collected and 
analyzed as according to the institution’s CLL flow cytometry MRD assay specifications. A 
second sample should be collected and processed for correlative studies. See the lab manual or 
correlative specimen for collection, processing and storage instructions.   
7.6.2 Bone Marrow Aspirate 
Any time a bone marrow biopsy is performed on this study after screening, at least two tubes of 
bone marrow aspirate will be collected for MRD testing. One sample will be collected and 
analyzed for CLL MRD by flow cytometry according to the institution’s laboratory specifications. 
A second sample should be collected and processed for correlative studies. See the lab manual 
or correlative specimen for collection, processing and storage instructions.   
Refer to the lab manual for sample collection and processing instructions. 
7.6.3 Pharmacokinetic Studies 
Plasma samples will be collected at defined time points in section 1.5.1 to assess the 
pharmacokinetics of RP-3500 and olaparib.  
7.6.3.1 On C1D1 and C1D15, blood samples will be collected at pre-dose and 0.5, 1, 2, 4, and 
24 hours post dose. Patients will take their doses of RP-3500 and olaparib in the infusion room 
or clinic after the pre-dose PK blood draw has occurred and at the instruction of the research 
team. For the 24 hour post dose collection, patients will have PK study blood drawn prior to 
taking their C1D2 and C1D16 drug doses.  
7.6.3.2 On C1D8, blood samples will be collected at pre-dose, 0.5, 1, 2, and 4 hours post dose. 
Patients will take their doses of RP-3500 and olaparib in the infusion room or clinic after the pre-
dose PK blood draw has occurred and at the instruction of the research team. 
 
Blood samples will be processed to plasma and RP-3500 and olaparib will be analyzed by 
validated LC/MS-MS bioanalytical methods. PK parameters for RP-3500 and olaparib will be 
calculated using non-compartmental analysis: area under the concentration-time curve (AUC) 
from time 0 to last quantifiable concentration (AUC0-last); AUC from time 0 to infinity (AUC0-inf); 
maximum observed plasma concentration (Cmax); time to reach Cmax (Tmax) and terminal 
elimination half-life (t1/2). The effect of olaparib on the AUC0-last and AUC0‐inf and Cmax of RP-3500 
will be compared to respective monotherapy doses from other studies performed with RP-3500. 
RP-3500 and olaparib may also be analyzed using population PK methods. 
7.7 
Remote Visits/Telehealth  
Some study visits and/or procedures may be conducted remotely in the following 
circumstances: 


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 
Telehealth visits do not present an increased risk to the participant. 
 
All necessary data for the trial can be collected. 
 
Procedures do not include research related imaging, lab samples, and/or pathology 
which should be conducted in person. 
The method of telehealth should be documented in the paricipants’ charts. 
8 
ADVERSE EVENTS 
8.1 
Definitions  
8.1.1 Adverse events 
21 CRF 312.32, ICH GCP, and OHRP define an adverse event as any untoward medical 
occurrence whether or not considered treatment-related. This definition extends to the worsening 
of any preexisting condition or symptom. All adverse events experienced during trial participation 
should be documented in the subject’s research chart and corresponding eCRF 
Laboratory abnormalities should not be listed as adverse events unless deemed clinically 
significant by the investigator or qualified designee. An abnormal test result or findings should not 
be recorded as an adverse event unless the following conditions are met: 
 
Associated with clinical symptoms; and/or 
 
Requires intervention (medical, surgical, or additional diagnostic testing); and/or 
 
Results in a change in study drug dosing; and/or 
 
Deemed by the investigator or qualified designee to be an adverse event. 
While disease progression should be noted in the subject’s research chart, it should not be 
reported as an adverse event. 
8.1.2 Serious Adverse Events 
 A serious adverse event is defined as any untoward event that is: 
 
Fatal; 
 
Life-threatening;(ie. the subject is at immediate risk of death, not at risk only if the event 
worsens or fails to respond to intervention) 
 
Results in persistent or significant disability/incapacity; 
 
Medically significant; 
 
Causes a congenital abnormality or birth defect; 
 
Requires or prolongs inpatient hospitalization. 
Investigator judgment must be used to assess an event as medically significant. The event may 
not be life-threatening or cause disability but may jeopardize the subject and require intervention 
to prevent the other SAE outcomes. 


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The following situations should not be reported as an SAE: 
 
Death due to disease progression; 
 
Hospitalization for signs and symptoms associated with disease progression; 
 
Hospital admission not associated with a precipitating AE such as: 
o Treatment for a preexisting condition not associated with a new AE or the 
worsening of a preexisting condition; 
o Admission for social or administrative reasons; 
o Optional admission or elective surgery; 
o Observation; 
o Preplanned treatments or surgical procedures as noted at baseline; 
o Admission for the administration of blood products. 
8.2 
Adverse Event Reporting
 
The investigator and qualified designees are responsible for the detection, documentation, 
reporting, and follow-up of all adverse events experienced by subjects during trial participation. 
AEs and SAEs will be recorded from the initiation of study therapy until 28 days after the last dose 
of study medication or until new cancer therapy is started. The following information will be 
required for each adverse event: 
 
Event term; 
 
For non-hematologic toxicities and patients with normal baseline platelet, hemoglobin and 
ANC, event severity as graded by the CTCAE v.5;  
 
For patients with baseline cytopenias (i.e. platelet count <100,000/mm3 and/or hemoglobin 
less than the lower limit of normal), hematologic toxicity event severity as graded by 2018 
iwCLL criteria (Refer to section 6.6.3) 
 
The causality assessment to study medication per the below definitions; 
 
Expectedness; 
 
Event duration; 
 
Any action taken to treat or manage the event; 
 
Event outcome. 
8.2.1 Severity Assessment 
The severity of adverse events should be assessed by CTCAE v.5. If an event is not listed in 
CTCAE v.5 then the assessment of severity should follow the general guidelines listed in Table 
18. 
 
 


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Table 18: Severity assessment  
Grade 
Severity Description  
1 
Mild event that generally does not require intervention. 
2 
Moderate event that may require intervention. 
3 
Severe event that requires intervention. 
4 
Life-threatening event that requires urgent intervention. 
5 
Death. 
Events meeting grade 4 or 5 severity description should be reported promptly as SAEs unless 
otherwise indicated in Section 8.1. 
8.2.2 Causality Assessment 
The Investigator should assess the causality or relationship of AEs and SAEs to study therapy. 
The Investigator should consider if there is evidence that the investigational product caused the 
event taking into consideration timing, organ system affected, type of event, and possible 
alternative etiologies. The relationship of the AE to study treatment will be reported as listed 
below. These categories will be defined as follows: 
 
Definitely related (D) – a clinical event, including laboratory test abnormality, occurring in 
a plausible time relationship to drug administration, and which cannot be explained by 
concurrent disease or other drugs or chemicals. The response to the withdrawal of the 
drug (dechallenge) should be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if 
necessary. 
 
Probably related (PR) – a reasonable time sequence to the administration of the drug, 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition. 
 
Possibly related (PO) – a reasonable time sequence to administrations of the drug, but 
which could also be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear. 
 
Unlikely related (UL) –a temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
 
Not related (NR) – there is no evidence of a causal relationship between the study drug 
and the event and in which other drugs, chemicals or underlying disease explain the event. 


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Adverse events reported as definitely, probably, and possible, related to study therapy will be 
reported as related. In cases when the Investigator is unsure of the causality of an AE, the event 
will be considered related to study therapy unless deemed otherwise by the DSMC. 
8.2.3 Expectedness 
The Investigator will be responsible for determining whether or not an adverse event was 
expected or unexpected. Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert (PI) or Reference Safety Information (RSI) of the current 
Investigator Brochure (IB). Unexpected adverse events are those not listed in the PI or current IB 
or not identified. This includes adverse events for which the specificity or severity is not consistent 
with the description in the PI or IB. For example, under this definition, hepatic necrosis would be 
unexpected if the PI or IB only referred to elevated hepatic enzymes or hepatitis. 
8.2.4  Action Taken and Outcome 
Start and stop dates will be required for all adverse events and serious adverse events. The action 
taken in response to the event should also be recorded in the subject’s research chart and 
corresponding eCRF. Event action terms include none, medication administered, non-drug 
therapy administered, surgery, hospitalization, or other with the option to specify. If a new 
medication is added the medication should also be added to the concomitant medications log. 
All adverse events should be followed until stabilization or resolution. Event outcomes may be 
classified as resolved, resolved with sequelae, ongoing, or death.  
8.2.5 Reporting Serious Adverse Events 
All serious adverse events should be reported as soon as possible but no later than one 
business day after the Investigator becomes aware. All SAEs must be reported via the HCI 
CTMS (OnCore) and submitted to HCI-RCO@utah.edu. The HCI Clinical Site Monitor will in 
turn, submit the report to the Medical Monitor. The RCO will summarize and present all reported 
SAEs according to the Data and Safety Monitoring Plan at the monthly DSMC meeting. 
At a minimum, initial SAE reports must include a description of the event, assessment of event 
causality, event grade, and the expectedness of the event. Although the Investigator may not 
know all the information at the time of the event, the available information should be reported. 
An SAE follow-up may be submitted at a later date once more information is known. It is 
required that follow-up reports be submitted until the SAE is resolved. 
Follow-Up Information 
It is recommended that follow-up reports be submitted as new information becomes available, 
however, a follow-up report should be submitted within 7 days of knowledge of event resolution. 
Follow-up information will be added to the SAE in OnCore and submitted to the DSMC via RCO.   
8.2.6 FDA Notifications 
Per 21 CRF 312.32 adverse events and serious adverse events will be reported on a MedWatch 
3500A form to the FDA. Reportable events will be reported by the RCO according to the 
following guidelines: 


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8.2.6.1 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic (Section A) and suspect medication 
information (Section C & D), the report should include the following information within the Event 
Description (Section B.5) of the MedWatch 3500A form: 
 
Protocol number and title description 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics (Section B.6) 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Expectedness of the event (i.e., expected or unexpected event). 
8.2.6.2 FDA Reporting Timelines: 
 
7 Calendar Day Report: 
Any event that is fatal or life-threatening, unexpected, and definitely, probably or possibly 
related to study medication will be reported to the FDA by telephone or fax within seven 
calendar days of first learning of the event. 
 
15 Calendar Day Report: 
Any event that is serious, unexpected, and definitely, probably or possibly related to 
study medication will be reported to the FDA in an IND safety report within 15 calendar 
days of first learning of the event. 
In accordance with 21 CFR 312.32, an Analysis of Similar Events should be included in 
the IND Safety Report. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in 
light of the previous, similar reports commented on. 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
8.2.7 IRB Notification 
The University of Utah IRB requires any unanticipated problems that may increase the risk to 
research participants be promptly reported. All study-therapy related, unexpected adverse events 
whose nature, severity, or frequency is not consistent with either: 
 
The unknown or foreseeable risk of adverse events that are described in the protocol 
related-documents, such as the IRB-approved research protocol, applicable investigator 
brochure, the current IRB-approved informed consent document, and/or other relevant 
sources of information, such as product labeling and package inserts; or 
 
The expected natural progression of any underlying disease or condition of the subject(s) 
experiencing the adverse event. 


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Adverse events meeting this criterion must be promptly reported to the IRB within 10 business 
days of awareness.  
8.2.8 Drug Manufacturer Notifications 
SAEs, regardless of causal relationship, as outlined in section 8.1 must be reported to Repare 
Therapeutics within one (1) business day of the Investigator’s knowledge of the event by 
submitting 
a 
completed 
SAE 
report 
form 
to 
rp-3500-safety@reparerx.com 
and 
reparesafety@navitaslifesciences.com. 
All Serious Unexpected Serious Adverse Reactions (SUSAR) shall be submitted to Repare 
Therapeutics at least 4 calendar days prior to the safety report (7/15 Day Safety Reports) due 
date.  SUSARS should be reported to rp-3500-safety@reparerx.com, 
reparesafety@navitaslifesciences.com, and pvg@drugsafetynavigator.com.  
8.3 
Special Situations  
8.3.1 Pregnancy or Breastfeeding  
Although pregnancy is not considered an adverse event, any exposure to the investigational 
products during pregnancy or breastfeeding must be reported promptly. Exposure may occur by 
a woman actively receiving study therapy or the partner of a male subject actively receiving study 
therapy becomes pregnant. Any possible pregnancy or breastfeeding exposure during study 
therapy and up to 28 days after the last dose of study therapy or up to the start of subsequent 
anticancer therapy (whichever happens first) must be reported within one business day of 
awareness regardless of the occurrence of an SAE. Should a woman on study therapy become 
pregnant, she should immediately discontinue study treatment. 
Women exposed to IP during pregnancy or while breastfeeding will be followed for pregnancy 
outcome and neonate health. Pregnancy outcomes may meet criteria as an SAE if ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly occurs. Congenital anomalies that occur in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death should be reported as an SAE. Any neonatal deaths 
that occur up to 30 days after birth or breastfeeding exposure should be reported as an SAE. 
Further follow-up on birth outcomes and neonate health will be handled on a case-by-case base. 
Pregnancies and any associated SAEs will be reported to Repare Therapeutics within one (1) 
business day of the Investigator’s knowledge of the pregnancy. 
8.3.2 Hy’s Law Cases 
It is important to identify possible cases of Drug-Induced Liver Injury (DILI) early. Total bilirubin, 
AST, and ALT should be regularly monitored for elevations indicative of liver damage. Subjects 
who experience a transaminase elevation above three times the ULN should be monitored 
frequently to determine if the elevation is transient. Transient elevations are an indication of 
adaption and these subjects may be identified as “adaptors.” However, should a transaminase 
elevation be followed by total bilirubin (TBili) increase, a DILI could be occurring. Any laboratory 
abnormalities meeting the following criteria should be reported within 24 hours of awareness: 
 
AST or ALT elevation > 3 x ULN; and 


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 
Total bilirubin > 2 x ULN; and 
 
Absence of cholestasis; and  
 
No alternative explanation for the elevations (e.g., impaired glucuronidation capacity 
caused by genetic [Gilbert syndrome]; viral hepatitis A, B, or C, preexisting or acute liver 
disease; or another drug capable of causing the observed injury). 
Investigators should conduct reasonable investigations to rule out other possible etiologies. 
Investigators should take into consideration the subject's use of ethanol, acetaminophen, 
recreational drugs, herbal supplements, and medical history. A potential Hy’s Law case will not 
be considered a confirmed case until all results and considerations have excluded alternative 
etiologies.  
Possible cases of DILI will be promptly reported to the FDA and Repare Therapeutics prior to full 
work up to rule out other etiologies. Reporting should be completed on a MedWatch 3500A form 
and should include all available information, including the likelihood that the drug caused the 
event. Subjects should be closely followed until the resolution of the event.  
Subjects who experience possible DILI should be managed per the Dose Modification Guidelines.  
8.4 
Data Safety Monitoring Committee  
A Data Safety Monitoring Committee (DSMC) at HCI is charged with ensuring the risk/benefit 
balance for subjects undergoing study therapy. The purpose of the DSMC is to ensure subject 
safety and make recommendations for study conduct to ensure subject safety and data integrity. 
The DSMC is chaired by a medical oncologist and may include, but is not limited to, 
representatives from medical oncology, oncological sciences, biostatistics, and pharmacy. 
The roles and responsibilities of the DSMC are described in the NCI-approved Data and Safety 
Monitoring (DSM) plan. The activities of the committee include reviewing adverse events 
(including SAEs), deviations, important medical events, and approving cohort/dose escalations. 
Amendments that increase risk, increase treatment exposure, or impact study objectives will also 
be reviewed by the DSMC. If the DSMC and/or the PI have concerns about unexpected safety 
issues or AE trends, the study may be stopped and an unplanned safety data analysis may be 
conducted. Enrollment will not resume until the issues are resolved. The DSMC also reviews and 
approves audit reports generated by the Research Compliance Office. 
All trials will be assigned and an oncologist member of the DSMC to serve as a medical monitor. 
In rare cases, an external medical monitor may be assigned. The Medical Monitor will be notified 
of all serious adverse events (SAEs). Specific notifications will also be issued when a dose-limiting 
toxicity is encountered and when the RP2D is defined. Approval from the Medical Monitor is 
required for all dose escalations. All serious adverse events (SAEs) occurring in subjects treated 
at HCI or its affiliates will also be reviewed by the full DSMC monthly.  
Each trial is assigned a research compliance officer who will be responsible for monitoring the 
trial and reporting to the DSMC. The assessed risk level of the trial will determine the frequency 
with which monitoring occurs. The Research Compliance Officer monitor will review the study 
status and summarize enrollment, toxicities, SAEs, dose-escalation, statistical endpoints (e.g., 


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stopping rules), deviations, and any other pertinent information for the full DSMC membership at 
the regularly scheduled meetings.  
Audits will be conducted for all trials one year after enrollment begins and annually thereafter. 
Audits may be conducted more frequently as requested by the DSMC, Institutional Review Board 
(IRB), Protocol Review and Monitoring Committee (PRMC), Research Compliance Office 
management, or the Principal Investigator.  
DSMC oversite will be tailored to the assessed risk level of the trial. Trials are categorized 
amongst three risk levels: high, moderate, and low.  
This trial has been classified as high risk and therefore will be monitored by RCO and reviewed 
by DSMC after the first subject is enrolled and then quarterly thereafter. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Sample size determination
 
9.1.1 Number of Patients Required for Dose Expansion 
Prior to amendment v. 28AUG2023, five patients were treated at the previous DL1 (camonsertib 
40mg daily and olaparib 100mg BID dosing 3 days per week). It was determined that this dosing 
strategy may not be appropriate for R/R CLL patients and reduced dosing may be necessary to 
increase safety of the combination therapy. These patients will be replaced and will not be 
included in the analysis. 
The planned sample size for dose expansion is 24 evaluable patients with a primary endpoint of 
overall response rate (ORR). In a recent phase I/II study of pirtobrutinib enrolling a similar CLL 
patient population, the ORR of the drug was 63%58. Therefore, the target ORR for the dose 
expansion portion of the trial will be 60%. ORR will be summarized by the observed proportion 
and an exact one-sided 95% confidence interval (Clopper-Pearson method). The estimated 
ORR and lower bounds of the confidence interval with 24 patients and ORR near 60% is 
presented in Table 19. With 24 evaluable patients, the lower bound of the confidence interval 
will be approximately 17-20% below the observed proportion for observed ORR near 60%, 
which is an acceptable level of precision in a dose expansion cohort. 
Table 19: Lower Bound of a One-sided 95% Confidence Interval for ORR with N = 24 Patients 
Lower Bound of a One-sided 95% Confidence Interval for ORR  with N = 24 Patients 
Number of Objective 
Responses 
Observed ORR 
Lower Bound of one sided 
95% Confidence Interval 
10 
42% 
24% 
11 
46% 
28% 
12 
50% 
31% 


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13 
54% 
35% 
14 
58% 
39% 
15 
63% 
43% 
16 
67% 
47% 
17 
71% 
52% 
18 
75% 
56% 
 
9.1.1.1 Enrichment of Dose Expansion with del(11q) and ATM Mutated Patients 
An enrichment cohort of 8 patients with either del(11q) and/or ATM mutation will be included in 
the arm A dose expansion cohort. If 8/8 patients in the enrichment cohort are responders, the 
lower bound of the exact one-sided 95% confidence interval will be 68.7%. If 7/8 are 
responders, the lower bound is 52.9%.  
9.2 
Populati on for Analyses  
A modified intent-to-treat data set will be used for both safety and efficacy endpoint analysis. All 
subjects who havereceived one dose of study medication will be included in all efficacy and safety 
data sets. Subjects who fail to begin study therapy will be replaced.  
9.2.1 DLT Evaluable Population 
For dose-finding, subjects who receive at least one dose of any study drug during the DLT 
evaluation period will be considered evaluable for a DLT event. Only subjects who have 
experienced a DLT event or received 80% of the expected doses during the DLT period will be 
included when evaluating dose level changes. 
9.2.2 Population for Sensitivity Analyses 
9.2.2.1 Per Protocol Analysis 
An additional analysis will be conducted including all subjects who have had an on treatment 
response assessment including imaging studies. All subjects without an on treatment response 
assessment will be excluded from this analysis.  
9.2.2.2 As-treated Analysis 
An as-treated analysis will be conducted including all subjects who have maintained at least 
75% medication compliance. Subjects who have missed over 25% of the required doses during 
study therapy for any reason other than for the management of treatment-related toxicities will 
not be evaluable for this analysis.  


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9.3 
Stopping Rules  
The trial will be evaluated quarterly for excess toxicity. A rate of 20% grade 3 or higher non-
hematological toxicity is acceptable, while a rate of 35% is unacceptable. Stopping boundaries 
were calculated using the R function “toxbdry” in the package “clinfun”. The trial will be stopped 
if more than 2/4, 3/8, 4/12, 5/16, 6/20, 7/24, 8/28 or 9/34 patients experience grade 3 or higher 
non-hematologic adverse events attributed to study therapy during the 12 month evaluation 
period.   
The operating characteristics of the stopping rule are difficult to determine precisely because up 
to 12 patients from the phase Ib portion will contribute to the phase II. We evaluated the 
operating characteristics in two ways. First, we present operating characteristics of the stopping 
rule calculated by toxbdry(0.16, 0.4, c(4,8,12,16,20,24,28,34),cP0=0.1, cP1=0.9, ngrid=7) in 
Table 20. This table assumes the operating characteristics are unaffected by the patients 
carried over from phase Ib to phase II. Second, we explore the effect of the rollover from phase 
Ib to phase II with a scenario in which the dose selection has a relatively large effect (Table 21). 
There are 3 assumptions: 1) 12 patients from the phase Ib portion contribute to phase II, 2) all of 
the grade 3 or higher non-hematologic toxicity occurred in the 28 day DLT period of phase Ib, 
and 3) the observed toxicity in the 12 rollover patients is in the target range of 25-35%. It is 
noted that the stopping probability in Table 21 is higher than the corresponding stopping 
probability in Table 20 when the true toxicity is lower than the target, and lower when the true 
toxicity is higher than the target. 
 
Table 20: Operating C haracte ristics of Stopping Rule
 from toxbdry  (N = 34)  
 
Table 21: Operating Characteristics of Stopping Rule Under Scenario (N = 34)
 
Operating Characteristics of Stopping Rule under the Scenario 
Described Above 
Operating Characteristics of Stopping Rule Calculated by toxbdry 
Probability of DLT 
Probability of 
Crossing Boundary 
Probability of 
Stopping Before Last 
Patient 
Expected Sample 
Size 
0.16 
8.9% 
7.9% 
32.3 
0.20 
21.1% 
18.0% 
30.4 
0.24 
38.9% 
32.8% 
27.6 
0.28 
58.4% 
50.1% 
24.1 
0.32 
75.5% 
66.7% 
20.5 
0.36 
87.6% 
80.2% 
17.2 
0.40 
94.6% 
89.6% 
14.3 


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Probability of DLT 
Probability of 
Crossing Boundary 
Probability of 
Stopping Before Last 
Patient 
0.16 
13.7% 
11.3% 
0.20 
26.3% 
20.7% 
0.24 
41.9% 
32.9% 
0.28 
58.9% 
47.3% 
0.32 
73.3% 
60.6% 
0.36 
84.4% 
72.8% 
0.40 
91.4% 
82.3% 
Should a treatment-related death occur on study, the trial will be stopped until all investigators 
and the DSMC can meet and determine appropriate actions. The event will be reported to the 
FDA. 
9.4 
Primary Endpoint s 
9.4.1 Dose-Finding 
The primary objective is to assess the RP2D and the rate of DLTs will be used to determine RP2D. 
All subjects who receive any study treatment will be included in the final summaries and listings 
of safety data. 
9.4.2 Overall Response Rate 
Overall response rate (ORR) will be calculated as the sum of subjects achieving any complete 
response (including CR and CRi) or any partial response (including PR and nPR) divided by the 
total number of response evaluable subjects. Subjects without a baseline/screening tumor 
assessment or at least one on-treatment assessment will be considered non-responders. Each 
value will be reported along with a one-sided 95% exact binomial confidence interval. No 
hypothesis testing will be performed for ORR. 
9.4.2.1 Rationale to Use ORR as Endpoint  
The decision to use ORR as the endpoint is based on multiple phase III clinical trials that have 
not shown a correlation between PFS and OS outcomes to CR rates. In Burger et al, elderly 
treatment-naïve CLL patients were randomized to receive either ibrutinib or chlorambucil35. CR 
rates for ibrutinib were 4% and 2% for chlorambucil yet ibrutinib had improved 18-month PFS and 
24-month OS by 38% (hazard ratio [HR] 0.16; 95% confidence interval [CI] 0.09 – 0.28; p<0.001) 
and 14% (HR 0.16; 95% CI 0.05 – 0.56; p=0.001), respectively. Similarly in R/R CLL patients, a 
phase III trial comparing ibrutinib vs. ofatumumab showed low CR rates of 2% and 1%, 
respectively33. In an updated analysis, ibrutinib-treated patients had a median PFS of 44.1 months 
as compared to 8.1 months for ofatumumab-treated patients (HR 0.148; 95% CI 0.113 – 0.196; 
p<0.001)59. Rituximab/venetoclax vs. rituximab/bendamustine was studied in the MURANO trial 
for R/R CLL patients34. Independent-review committee CR rates for rituximab/venetoclax was 


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8.2% as compared to 3.6% for patients treated with rituximab/bendamustine. An updated 36 
month median follow up showed an improvement in 36 month PFS of 56.2% (HR 0.16; 95% CI 
0.12 – 0.23; p<0.001) for patients treated with rituximab/venetoclax as compared to patients 
treated with rituximab/bendamustine as well as 36 month OS of 87.9% vs. 79.5% (HR 0.50; 95% 
CI 0.30 – 0.85; p=0.0093). Lastly, precedence to use ORR as the primary endpoint for a R/R CLL 
phase II trial exists with venetoclax60. 
9.5 
Secondary Endpoints  
9.5.1 Safety and Tolerability 
All subjects who receive any study treatment will be included in the final summaries and listings 
of safety data. The detailed information collected for each AE will include a description of the 
event, duration, severity, relatedness to study drugs, action taken, and clinical outcome. The 
severity of the AEs will be graded according to the CTCAE v5.0. The statistical analysis of the 
safety data will be descriptive and tabular. 
9.5.2 Duration of Response 
The duration of response (DoR) will be defined as the time from the first documented response 
(CR, CRi, PR or nPR per iwCLL) until the time of progression, the start of a new therapy, or death 
from any cause. Kaplan-Meier methods will be used to analyze DoR and will be presented with 
95% confidence intervals. Table 22 defines the date of progression or censoring that will be 
utilized for the analysis. No formal hypothesis testing will be performed. 
Table 22: Duration of Response Censoring Criteria  
Situation  
Date of Progression or Censoring
 
Outcome  
Incomplete or no baseline 
tumor assessments 
Date of registration 
Censored 
Progression documented 
between scheduled visits 
Earliest of: 
 
Date of progression assessment 
showing new lesion (if progression is 
based on new lesion); 
or 
 
Date of last progression assessment. 
Progressed 
No progression 
Date of last progression assessment with no 
documented progression 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last progression assessment with no 
documented progression 
Progressed 
New anticancer treatment 
started 
Date of last progression assessment with 
documented non-progression before the start of 
new treatment 
Progressed 


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Death before first PD 
assessment 
Date of death  
Progressed 
Death between adequate 
assessment visits  
Date of death  
Progressed 
Death or progression after 
more than one missed visit 
Date of last progression assessment with 
documented non-progression 
Progressed 
9.5.3 Progression-Free Survival  
Progression-free survival (PFS) will be defined as the time from treatment initiation until 
documented clinical or radiographic progression or death from any cause. Kaplan-Meier methods 
will be used to analyze PFS and will be presented with 95% confidence intervals. Table 23 defines 
the date of progression or censoring that will be utilized for the analysis. No formal hypothesis 
testing will be performed.  
Table 23: PFS Censoring Criteria  
Situation  
Date of Progression or Censoring
 
Outcome  
Incomplete or no baseline 
tumor assessments 
Date of treatment initiation 
Censored 
Progression documented 
between scheduled visits 
Earliest of: 
 
Date of progression assessment 
showing new lesion (if progression is 
based on new lesion); 
or 
 
Date of last progression assessment. 
Progressed 
No progression 
Date of last progression assessment with no 
documented progression 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last progression assessment with no 
documented progression 
Progressed 
New anticancer treatment 
started 
Date of last progression assessment with 
documented non-progression before the start of 
new treatment 
Progressed 
Death before first PD 
assessment 
Date of death  
Progressed 
Death between adequate 
assessment visits  
Date of death  
Progressed 


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Death or progression after 
more than one missed visit 
Date of last progression assessment with 
documented non-progression 
Progressed 
9.5.4 Overall Survival 
Overall Survival (OS) will be assessed as the time between treatment initiation and death of any 
cause. Subjects will be followed for OS for at least seven years after the initiation of therapy until 
death from any cause. Subjects lost to follow-up will be censored at the time of last known follow-
up. Subjects still alive will be censored after five years from the date of study therapy initiation. 
Kaplan-Meier methods will be used to analyze OS. No hypothesis formal testing will be performed 
for OS.  
10 ETHICAL AND REGULATORY CO NSIDERATIONS 
10.1 Human Subjects Protection
 
The study will be conducted in accordance with the protocol, 21 CFR, HIPAA regulations, the 
Belmont Principles, ICH Guidelines for Good Clinical Practice (GCP), and the Declaration of 
Helsinki. Informed consent will be obtained from all research participants or their legally 
authorized representative before performing any study procedures using the most recent IRB 
approved version.  
10.1.1 Personal Data Protection 
All parties will take all necessary actions required for the protection of subject personal data. 
Subjects enrolled in the study will be assigned a subject number and will be reference by this 
number. Directly identifiable data will be omitted from reports, publications, and other disclosures. 
All personal data will be store at the study site in encrypted electronic and/or paper form stored in 
a locked and secured facility. The site will be responsible for maintaining a list of subjects linking 
each subject with their subject number. Data will only be accessed by appropriate personnel and 
will be password protected or securely stored in a locked room. In the case of a potential breach 
of personally identifiable data, the site will take responsibility to ensure appropriate action is taken 
according to institutional practice and applicable laws and regulations.  
10.2 Institutional Review  
Before the initiation of the study, the Investigator will have prospective approval of the study 
protocol, protocol amendments, informed consent documents, and other relevant documents, 
(e.g., recruitment advertisements, questionnaires, if applicable), from the IRB. All correspondence 
with the IRB should be retained in the Investigator’s regulatory file. Changes to the protocol or 
approved documents may not be made until IRB approval has been received. However, if a 
change is necessary to eliminate immediate hazards to the subjects, prospective approval is not 
necessary.  
The investigator or designee should provide the IRB with reports, updates and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 


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10.3 Investigator Responsibilities
 
The Investigator is responsible for ensuring the trial is conducted in compliance with the current 
IRB approved version of the protocol, GCP, the Declaration of Helsinki, and any applicable 
national and local laws and regulations.   
10.4 Protocol Amendments
 
Any amendments or administrative changes to an IRB approved protocol will not be initiated 
without submission of an amendment for IRB review and approval. However, prospective IRB 
approval will not be sought when an amendment is required to eliminate immediate risk to subjects 
on study. In these cases, amendments will be retrospectively submitted to the IRB for review and 
approval. 
Any amendments to the protocol that significantly affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the study will be submitted to the FDA for review. 
10.5 Protocol Deviations  
A deviation will be defined as any noncompliance with ICH GCP or the clinical protocol 
requirements. The noncompliance may be either on the part of the participant, the Investigator, 
or the study staff. As a result of the deviation, a corrective action must be implemented to ensure 
future deviation does not occur. It is the Investigator’s responsibility to identify and report 
deviations from ICH GCP or protocol requirements. These deviations and corrective action should 
be documented in the subject’s research chart, the associated eCRF, and reported to the IRB per 
their policy.  
10.6 FDA Reporting   
As applicable and in accordance with 21 CRF 312.33, an annual progress report will be submitted 
to the FDA within 60 days of the anniversary of the date the IND went into effect.  
11 DATA HANDLING  
11.1 Recording and Collection of Data
 
Primary source documentation will come directly from the subject’s medical record. All source 
documentation should be attributable, legible, contemporaneous, original, accurate, complete, 
and available. All documentation should be signed and dated by applicable personnel. Relevant 
source data will be transcribed into the electronic case report forms (eCRFs) and should be 
completed as soon as possible after data availability. The eCRFs will be part of a computerized 
database grounded in the protocol requirements and study objectives. The database will be 
designed to comply with 21 CFR Part 11.  
The Investigator has ultimate responsibility for ensuring that all data collected and recorded is 
accurate and consistent. He/she will need to sign off on all eCRFs to attest that all data recorded 
on them is true. A separate screening log of all the subjects screened for participation in the study 
must also be maintained and should include gender, age, eligibility status, the reason for 
ineligibility (if applicable), and study allocated subject number (if applicable). 


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11.2 Data Management  
To accommodate evaluations, inspections, and/or audits from regulatory authorities, the 
Investigator must maintain all study records including subject identity, source documentation, 
original signed consent form, safety reporting forms, monitoring logs, IP accountability records, 
relevant correspondence (e.g., letters, emails, meeting minutes, etc.), and any other documents 
pertaining to the conduct of the study. The Investigator must also agree to the maintain source 
documents for a minimum of two years after regulatory approval of the investigational product per 
21 CFR 312.57. For the duration of record maintenance, records must be stored in a secure 
location and protected from the elements. If for any reason the Investigator at another participating 
institution is no longer able to retain study records, the HCI Investigator Sponsor should be notified 
before any destruction so that the records can be transferred to an acceptable designee. Once 
retention requirements have been met, the participating site Investigator must get HCI Investigator 
Sponsor approval before the destruction of any records.  
12 PUBLICATION PLAN  
In accordance with U.S. regulations and the best interest of research ethics and transparency, 
this study will be registered on ClinicalTrials.gov before subject enrollment. US Basic Results will 
also be reported and available on ClinicalTrials.gov within one year of the primary completion 
date, regardless of formal journal publication. All results will be reported objectively, accurately, 
balanced, and completely, regardless of the study outcome.  
 
 


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3. 
Takahashi K, Hu B, Wang F, et al: Clinical implications of cancer gene mutations 
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6. 
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Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in 
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Eichhorst B, Fink AM, Bahlo J, et al: First-line chemoimmunotherapy with 
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16. 
Knittel G, Rehkamper T, Korovkina D, et al: Two mouse models reveal an 
actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun 
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18. 
Pratt G, Yap C, Oldreive C, et al: A multi-centre phase I trial of the PARP inhibitor 
olaparib in patients with relapsed chronic lymphocytic leukaemia, T-prolymphocytic leukaemia 
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19. 
Pilie PG, Tang C, Mills GB, et al: State-of-the-art strategies for targeting the DNA 
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Ashworth A, Lord CJ: Synthetic lethal therapies for cancer: what's next after 
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Robson M, Goessl C, Domchek S: Olaparib for Metastatic Germline BRCA-
Mutated Breast Cancer. N Engl J Med 377:1792-3, 2017 
 
22. 
Robson M, Im SA, Senkus E, et al: Olaparib for Metastatic Breast Cancer in 
Patients with a Germline BRCA Mutation. N Engl J Med 377:523-533, 2017 
 
23. 
Litton JK, Rugo HS, Ettl J, et al: Talazoparib in Patients with Advanced Breast 
Cancer and a Germline BRCA Mutation. N Engl J Med 379:753-763, 2018 
 
24. 
Lord CJ, Ashworth A: PARP inhibitors: Synthetic lethality in the clinic. Science 
355:1152-1158, 2017 
 
25. 
Kim H, George E, Ragland R, et al: Targeting the ATR/CHK1 Axis with PARP 
Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models. Clin Cancer 
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26. 
Yazinski SA, Comaills V, Buisson R, et al: ATR inhibition disrupts rewired 
homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-
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Wan Y, Wu CJ: SF3B1 mutations in chronic lymphocytic leukemia. Blood 
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Te Raa GD, Derks IA, Navrkalova V, et al: The impact of SF3B1 mutations in 
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Turner JG, Dawson J, Sullivan DM: Nuclear export of proteins and drug 
resistance in cancer. Biochem Pharmacol 83:1021-32, 2012 
 
30. 
Jeromin S, Weissmann S, Haferlach C, et al: SF3B1 mutations correlated to 
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31. 
Poncet D, Belleville A, t'kint de Roodenbeke C, et al: Changes in the expression 
of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic 
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32. 
Ramsay AJ, Quesada V, Foronda M, et al: POT1 mutations cause telomere 
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33. 
Byrd JC, Brown JR, O'Brien S, et al: Ibrutinib versus ofatumumab in previously 
treated chronic lymphoid leukemia. N Engl J Med 371:213-23, 2014 
 
34. 
Seymour JF, Kipps TJ, Eichhorst B, et al: Venetoclax-Rituximab in Relapsed or 
Refractory Chronic Lymphocytic Leukemia. N Engl J Med 378:1107-1120, 2018 
 
35. 
Burger JA, Tedeschi A, Barr PM, et al: Ibrutinib as Initial Therapy for Patients 
with Chronic Lymphocytic Leukemia. N Engl J Med 373:2425-37, 2015 
 
36. 
Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and Obinutuzumab in Patients 
with CLL and Coexisting Conditions. N Engl J Med 380:2225-2236, 2019 
 
37. 
Mato AR, Barrientos JC, Ghosh N, et al: Prognostic Testing and Treatment 
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Hillmen P, Rawstron AC, Brock K, et al: Ibrutinib Plus Venetoclax in 
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39. 
Wierda WG, Byrd JC, Abramson JS, et al: NCCN Guidelines Insights: Chronic 
Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019. J Natl Compr Canc 
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40. 
Burger JA, Sivina M, Jain N, et al: Randomized trial of ibrutinib vs ibrutinib plus 
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41. 
Byrd JC, Hillmen P, Ghia P, et al: Acalabrutinib Versus Ibrutinib in Previously 
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42. 
Brown JR: How I treat CLL patients with ibrutinib. Blood 131:379-386, 2018 
 
43. 
Pommier Y, O'Connor MJ, de Bono J: Laying a trap to kill cancer cells: PARP 
inhibitors and their mechanisms of action. Sci Transl Med 8:362ps17, 2016 
 
44. 
Moore K, Colombo N, Scambia G, et al: Maintenance Olaparib in Patients with 
Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 379:2495-2505, 2018 
 
45. 
Ray-Coquard I, Pautier P, Pignata S, et al: Olaparib plus Bevacizumab as First-
Line Maintenance in Ovarian Cancer. N Engl J Med 381:2416-2428, 2019 
 
46. 
Pujade-Lauraine E, Ledermann JA, Selle F, et al: Olaparib tablets as 
maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a 
BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, 
phase 3 trial. Lancet Oncol 18:1274-1284, 2017 
 
47. 
Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in 
platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382-92, 2012 
 
48. 
Golan T, Hammel P, Reni M, et al: Maintenance Olaparib for Germline BRCA-
Mutated Metastatic Pancreatic Cancer. N Engl J Med 381:317-327, 2019 
 
49. 
de Bono J, Mateo J, Fizazi K, et al: Olaparib for Metastatic Castration-Resistant 
Prostate Cancer. N Engl J Med 382:2091-2102, 2020 
 
50. 
Fong PC, Boss DS, Yap TA, et al: Inhibition of poly(ADP-ribose) polymerase in 
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51. 
Kaye SB, Lubinski J, Matulonis U, et al: Phase II, open-label, randomized, 
multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase 
inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and 
recurrent ovarian cancer. J Clin Oncol 30:372-9, 2012 
 
52. 
LYNPARZA® (olaparib) [package insert]. Wilmington, DE: AstraZeneca 
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53. 
Yan F, Mandrekar SJ, Yuan Y: Keyboard: A Novel Bayesian Toxicity Probability 
Interval Design for Phase I Clinical Trials. Clin Cancer Res 23:3994-4003, 2017 
 
54. 
Ji Y, Liu P, Li Y, et al: A modified toxicity probability interval method for dose-
finding trials. Clin Trials 7:653-63, 2010 
 
55. 
Hallek M, Cheson BD, Catovsky D, et al: iwCLL guidelines for diagnosis, 
indications for treatment, response assessment, and supportive management of CLL. Blood 
131:2745-2760, 2018 
 
56. 
Roberts AW, Davids MS, Pagel JM, et al: Targeting BCL2 with Venetoclax in 
Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 374:311-22, 2016 
 
57. 
Berger MJ, Ettinger DS, Aston J, et al: NCCN Guidelines Insights: Antiemesis, 
Version 2.2017. J Natl Compr Canc Netw 15:883-893, 2017 
 
58. 
Mato AR, Shah NN, Jurczak W, et al: Pirtobrutinib in relapsed or refractory B-cell 
malignancies (BRUIN): a phase 1/2 study. Lancet 397:892-901, 2021 
 
59. 
Munir T, Brown JR, O'Brien S, et al: Final analysis from RESONATE: Up to six 
years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or 
small lymphocytic lymphoma. Am J Hematol 94:1353-1363, 2019 
 
60. 
Stilgenbauer S, Eichhorst B, Schetelig J, et al: Venetoclax in relapsed or 
refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 
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61. 
Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. American journal of clinical oncology 5:649-655, 1982 
 
 
 


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Appendix 1: ECOG Performance Status
61 
 
Score  
Definition  
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hour 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care. Confined to bed or chair 
5 
Dead 
 
 
 


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Appendix 2: Rai and Binet Staging System  
Risk Level  
Rai 
Stage 
Description  
Low-Risk 
Disease 
0 
Lymphocytosis; no enlargement of the lymph nodes, spleen, or liver; 
red blood cell and platelet counts are near normal. 
Intermediate 
Risk 
I 
Lymphocytosis; enlarged lymph nodes; spleen and liver are not 
enlarged; red blood cell and platelet counts are near normal. 
II 
Lymphocytosis; enlarged spleen (and maybe an enlarged liver); 
lymph nodes may or may not be enlarged; red blood cell and platelet 
counts are near normal. 
High Risk 
III 
Lymphocytosis; lymph nodes, spleen, or liver may or may not be 
enlarged; red blood cell counts are low (anemia); platelet counts are 
near normal. 
IV 
Lymphocytosis; enlarged lymph nodes, spleen, or liver; red blood 
cell counts may be low or near normal; platelet counts are low 
(thrombocytopenia). 
 
 
Binet Stage Description  
A 
Two or less lymphoid bearing areas enlarged* 
B 
Three or more lymphoid bearing areas enlarged* 
C 
Presence of anemia (hemoglobin <10 g/dL) or thrombocytopenia (platelet count 
<100,000/mm3) 
* Five lymphoid beraing areas are possible: cervical, axillary, inguino-femoral, spleen and liver. 


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Appendix 3: Subject  Dosing Diary  
Subject Number: _______________________ 
 
 
Date: __________________ 
Cycle #:________ 
Please record how many tablets you take of the study medications, the time you take them, and 
bring the completed diary as well as your study drug supply, including empty bottles, to every 
study visit. This diary will help us keep track of your study drug and how well you are tolerating 
it. 
Storage Instructions:
 
RP-3500- Store at room temperature. Keep out of reach of children. 
Olaparib- Store at room temperature. Keep out of reach of children.  
Administration  Instructions:  
RP-3500- Take with 8 oz of water at approximately the same time each day (±2 hours).  
Olaparib- Take with 8 oz of water at approximately the same time each day (±2 hours). 
General  Instructions:  
Study medication should not be crushed, chewed, or altered in any way. Do not take extra 
medication for any reason nor should you re-administer in the case of vomiting after 
administration. If a dose is missed outside of the dosing window, the dose should not be made up 
but rather take your next dose at you regularly scheduled time. 
You will take the following number of tablets each time (per dose) as listed in the table below: 
 
Study Drug Name  
# of tablets to 
take per 
time/dose  
# of 
times/doses 
each day  
Time of Dose  
(To be completed below)  
RP-3500 
______ tablet(s) 
(____mg)  
Once daily; 2 
days on and 
5 days off 
____:____ 
 a.m.  
 p.m. 
 
Olaparib  
______ tablets 
(____mg)  
Twice daily; 
2 days on 
and 5 days 
off 
____:____ 
 a.m.  
 p.m. 
____:____ 
 a.m.  
 p.m. 
 
 
 


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Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
  
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments:  
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
  
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments:  
 
RP-3500 
 
  
 
  
Olaparib  
 
  
 
  
Comments:  
 
RP-3500 
 
  
 
  


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Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
Olaparib  
 
  
 
  
Comments:  
 
RP-3500 
 
  
 
  
Olaparib  
 
  
 
  
Comments:  
 
RP-3500 
 
 
 
 
Olaparib  
 
  
 
 
 
 
 
 
 
  
Comments:  
 
RP-3500 
 
 
  
 
 
 
 
  
Olaparib  
 
 
 
 
 
 
 
 
 
  
Comments:  


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Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
  
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
 ______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments: 
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
  
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments:  
 
RP-3500 
 
  
 
 
 
 
 
  
Olaparib  
 
  
 
 
 
 
 
 
 
  
 
Comments:  


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Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
 
RP-3500 
 
 
 
 
Olaparib  
 
  
 
  
Comments:  
 
RP-3500 
 
 
 
 
Olaparib  
 
 
 
  
Comments: 
 
RP-3500 
 
 
 
 
Olaparib  
 
 
 
 
 
Comments:  
 
RP-3500 
 
 
  
 
  
Olaparib  
 
 
 
 
  
 
  
Comments:  


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Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
  
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments:  
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
  
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments: 
 
RP-3500 
 
  
 
  
Olaparib  
 
  
 
  
 
Comments:  
 
RP-3500 
 
 
 
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 109 of 113 
Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
Olaparib  
 
  
 
  
Comments:  
 
RP-3500 
 
 
 
 
Olaparib  
 
  
 
  
Comments: 
 
RP-3500 
 
 
 
 
Olaparib  
 
  
 
  
Comments:  
 
RP-3500 
 
 
 
  
 
  
Olaparib  
 
 
 
 
 
 
  
 
  
Comments:  


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 110 of 113 
Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
   
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments:  
 
RP-3500 
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
  
Olaparib  
 
______:______ 
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
 
______:______   
□ a.m. / □ p.m. 
□ Dose Not 
Taken   
Comments: 
 
RP-3500 
 
  
 
  
Olaparib  
 
  
 
  
Comments:  
 
RP-3500 
 
 
 
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 111 of 113 
Date 
Medication  
Number 
of 
Tablets 
Taken 
Time of Dose  
Number 
of 
Tablets 
Taken 
Time of 
Dose 
Olaparib  
 
  
 
 
Comments:  
 
RP-3500 
 
 
 
 
Olaparib  
 
  
 
 
Comments: 
 
RP-3500 
 
 
 
 
Olaparib  
 
  
 
 
Comments:  
 
RP-3500 
 
  
 
  
Olaparib  
 
  
 
  
Comments:  
 
Participant/Caregiver Signature: _______________________________   
Date:_______________ 
 
 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 112 of 113 
 
Appendix 4: Examples of  Strong CYP3A Inhibitors and Inducers, P
-GP Inhibitors and 
BCRP Inhibitors  
Strong CYP3A Inhibitors
 
Inhibitor  
Therapeutic Class  
ritonavir 
Protease Inhibitors 
cobicistat (GS-9350) 
None 
ketoconazole 
Antifungals 
troleandomycin 
Antibiotics 
telaprevir 
Antivirals 
itraconazole 
Antifungals 
indinavir 
Protease Inhibitors 
voriconazole 
Antifungals 
mifepristone 
Antiprogestins 
clarithromycin 
Antibiotics 
posaconazole 
Antifungals 
telithromycin 
Antibiotics 
grapefruit juice  
Food Products 
ceritinib 
Kinase Inhibitors 
conivaptan 
Diuretics 
nefazodone 
Antidepressants 
nelfinavir 
Protease Inhibitors 
saquinavir 
Protease Inhibitors 
ribociclib 
Kinase Inhibitors 
idelalisib 
Kinase Inhibitors 
boceprevir 
Antivirals 
 
Strong CYP3A Inducers  
Inducers  
Therapeutic class  
rifampin 
Antibiotics 
mitotane 
Other Antineoplastics 
avasimibe 
Other Antilipemics 
rifapentine 
Antibiotics 


Protocol: CORONADO 
Version: 28AUG2023 
 
Page 113 of 113 
Inducers  
Therapeutic class  
apalutamide 
Antiandrogens 
ivosidenib 
Cancer Treatments 
phenytoin 
Anticonvulsants 
carbamazepine 
Anticonvulsants 
enzalutamide 
Antiandrogens 
St John's Wort extract 
Herbal Medications 
lumacaftor 
Cystic Fibrosis Treatments 
phenobarbital 
Anticonvulsants 
 
P-gp Inhibitors:  
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, propafenone, 
quinidine, ranolazine, ritonavir, telaprevir, verapamil 
 
BCRP Inhibitors:  
curcumin, cyclosporine A, eltrombopag