A Phase II, Open-Label, Study of Olaparib in Combination With Either Durvalumab (MEDI4736), Selumetinib or Capivasertib, or Ceralasertib Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer
Phase: PHASE2
Conditions: Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Triple-Negative Breast Carcinoma
Sponsor: Gordon Mills, MD, PhD

 
0 
 
Study Title: 
A Phase II, Open-Label, Study of Olaparib in combination with 
either Durvalumab (MEDI4736), Selumetinib or Capivasertib, or 
Ceralasertib monotherapy in Patients with Metastatic Triple-
Negative Breast Cancer 
Protocol Number:  18504 
ClinicalTrials.gov ID:  NCT03801369 
Investigational product: Olaparib, Durvalumab, Selumetinib, Capivasertib, Ceralasertib  
Version Number:  9.2 
Version Date: 10 Apr 2023 
Replaces: 9.1 
Principal Investigator: Alexandra Zimmer, MD, MSc 
 
Division of Hematology and Medical Oncology 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, OC14HO  
Portland, OR 97239  
Phone: 503-494-6594 
Email: hobbev@ohsu.edu 
 
Co-Investigator(s): 
Janelle Meyer, MD 
Oregon Oncology Specialists 
875 Oak Street, Suite 4030 
Salem, OR 97301-3984 
Phone: 503-561-6444 
Email: jmeyer@orcancer.com  
 
Douglas Yee, MD 
Masonic Cancer Center, University 
of Minnesota 
420 Delaware Street SE 
MMC 806 
Minneapolis, MN 55455 
Phone: 612-626-8487 
Email: yeexx006@umn.edu 
Jennifer Specht, MD 
Seattle Cancer Care Alliance 
825 Eastlake Ave E, G3630 
Seattle, WA 98109-1023 
Phone: 206-606-2053 
Email: jspecht@uw.edu  
 
Ben Ho Park, MD PhD 
Vanderbilt University Medical Center 
2220 Pierce Avenue, Preston 
Research Building, Rm 770 
Nashville, TN 37232 
Phone: 615-936-1919 
Email: ben.h.park@vumc.org 
Statistician: 
Lim, Jeong Youn, PhD  
Biostatistics Shared Resource, 
Knight Cancer Institute 
Oregon Health & Science University 
2730 SW Moody Ave, KR-BSR  
Phone: 503-494-7062 
Fax: 503-346-6931 
Email: limje@ohsu.edu  
 

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
1 
SUMMARY OF CHANGES 
 
# 
Section 
Change 
Justification 
2.0 
 
1 
Revised language 
Background language has been revised 
to include additional information 
regarding immunotherapies, olaparib 
and durvalumab 
2.0 
1.5.1 
Added additional risk language 
Risk language regarding immune 
checkpoint blockade has been added 
per manufacturer recommendation 
2.0 
2.2, 2.3 
Revised language 
Objectives revised for clarity to align 
with study endpoints 
2.0 
3.1.1 
Added scientific rationale for study 
design 
Language in study design has been 
revised for clarity 
2.0 
3.1.1, 3.2.2, 
6.3.3, 7.13 
Changed to CTCAE v5.0 
CTCAE 4.03 has been updated to 
CTCAE 5.0 
2.0 
3.2 
Endpoints table revised for clarity 
Endpoints times, start and stop, have 
been revised for clarity. Objectives have 
been added to align with endpoints.   
2.0 
4.1, 4.2 
Inclusion criteria revised  
Inclusion criteria revised for clarity 
2.0 
4.1 
Inclusion life expectancy changed 
from >6 months to ≥16 weeks 
Given the inclusion criteria allow up to 2 
lines of therapy in the metastatic 
setting, and average survival for 
metastatic TNBC is around 15 months, 
16 weeks expected life expectancy is 
more appropriate for this study.  
2.0 
4.2 
Added exclusion criterion of: 
Participants with germline BRCA 
mutated TNBC will be excluded 
Olaparib is FDA approved for treatment 
of metastatic BRCA mutated breast 
cancer. Additionally, this combination is 
being actively investigated in a separate 
trial for patients with metastatic BRCA 
mutated breast cancer. 
2.0 
4.2 
Added exclusion criterion of: 
Participants with myelodysplastic 
syndrome/acute myeloid leukemia 
or with features suggestive of 
MDS/AML. 
Olaparib is associated with increased 
risk of MDS/AML, participants with 
MDS/AML are being excluded to 
minimize risk of disease exacerbation 
2.0 
4.2 
Revised poor medical health 
exclusion criteria 
Exclusion criteria for participants with 
poor medical health revised for clarity 
2.0 
4.2 
Addition of exclusion criteria 
deferring to investigator 
Exclusion criteria deferring to 
investigator added for clarity and safety 
2.0 
4.2.1 
Revised exclusion criteria 
Exclusion criteria is revised for clarity 
and minimize participant risk 
2.0 
5.1.1, 5.2.1 
Revised drug acquisition for 
olaparib and durvalumab 
Revised language for acquisition of 
olaparib and durvalumab 
2.0 
5.1.8 
Revised administration language 
Language for revised clarity 
2.0 
5.2.2 
Updated language 
Formulation packaging language 
revised per manufacturer 
recommendation 
2.0 
5.2.5, 5.2.6, 
5.2.7.1 
Updated language 
Language revised per manufacturer 
recommendation 

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
2 
# 
Section 
Change 
Justification 
2.0 
6.3.1, 6.3.1.1, 
6.3.16, 6.3.2, 
6.3.3 - 6.6.2 
Updated language to toxicity 
management and supportive care 
Language revised per manufacturer 
recommendation 
2.0 
7.4.3 
Addition of fecal sample collection 
Study added to characterize 
microbiome as part of understanding 
tumor resistance based on recent 
literature findings:  
Gopalakrishnan V,et al. Science. 
2017;359(6371):97-103.   
2.0 
8.5.5 
Added section “Confirmation of 
Progression Guidelines” 
Confirmation of progression guidelines 
have been added i) for participant 
management and treatment decisions, 
and ii) in the absence of significant 
clinical deterioration, to promote the 
collection of additional scans after the 
first radiologic RECIST 1.1 assessment 
of PD to distinguish pseudoprogression 
from true radiologic progression 
2.0 
9.2.1 
Adverse Events 
Language updated for clarity 
2.0 
9.2.2 
Serious Adverse Events 
Language updated for clarity 
2.0 
9.4.2 
Olaparib Adverse of Events of 
Special Interest 
Language added per manufacturer 
recommendation 
2.0 
9.4.3 
Durvalumab Adverse of Events of 
Special Interest 
Language added per manufacturer 
recommendation 
2.0 
9.5 
Additional criteria added to AE 
assessment 
Language added per manufacturer 
recommendation 
2.0 
9.5.1 
Adverse events after the 90 day 
follow up period 
Language added per manufacturer 
recommendation 
2.0 
9.6, 9.6.1, 
9.6.2 
Added Overdose language for 
olaparib and durvalumab 
Additional safety reporting language 
added 
2.0 
9.7 
Revised MedWatch reporting 
language 
Revised language to include instruction 
for manufacturer reporting 
2.0 
9.8 
Added Section “Reporting of deaths 
to AstraZeneca” 
Added language to include instruction 
for manufacturer reporting 
2.0 
10.1, 10.2.2, 
10.2.3.2, 
10.3.2.1 
Revised language 
Statistical language revised for clarity 
2.0 
10.2.4 
Addition of Analysis of Exploratory 
Endpoints 
Statistical language added for 
exploratory endpoints 
2.0 
11.1 
Revised language 
Language revised for clarity 
2.0 
12.3 
Added REDCap Cloud EDC 
Revised to include description of 
REDCap Cloud EDC 
2.0 
12.5.1 
Added specimen/data sharing 
language 
Additional specimen/data sharing with 
existing observational study, MMTERT, 
IRB#16113 
2.0 
13.1, 13.5 
Revised language 
Revised for clarity  
2.0 
Appendix A 
Revised language 
Revised for clarity 
2.0 
Appendix C 
Revised language 
Revised language per manufacturer 
recommendations 
2.0 
Appendix H 
Addition of Hy’s Law 
Language added for identification/ 
actions required in cases of increases in 

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
3 
# 
Section 
Change 
Justification 
liver biochemistry and evaluation of 
Hy’s law cases 
3.0 
Overview 
Updated the address for the 
Statistician 
Contact information for Biostatistics 
Shared Resources updated  
3.0 
7.13 Schedule 
of Events 
Collection of Tumor Markers 
updated 
Collection of tumor markers on C1D15 
and C2D15 has been added to monitor 
response to therapy by liquid blood 
biomarkers.  Tumor markers are 
needed at the end of treatment to 
correlate liquid blood-based biomarkers 
to imaging to evaluate response to 
therapy. 
3.0 
7.13 Schedule 
of Events 
Fecal Sample collection moved 
from follow-up to end of treatment in 
the schedule of events 
The schedule of events was updated to 
align with Section 7.4.3.  Fecal samples 
are to be collected at screening, before 
starting durvalumab, and at the time of 
disease progression.    
4.0 
4.2 
Exclusion criteria #5 revised to state 
“Participant received prior 
chemotherapy within the past 28 
days, prior targeted therapies within 
the past 14 days, or radiation 
(except for palliative reasons) within 
the past 3 weeks, prior to first day 
of treatment” 
Exclusion criteria incorrectly stated 
limitation on prior therapy within past 3 
weeks prior to going on study.  A 
washout period of 14 days is sufficient 
to allow recovery from the side effects 
of targeted therapies.    
4.0 
7.4.2 
Blood collection to occur at OHSU 
and CHO 
Amended to correctly state that blood 
collection occurs at both OHSU and 
CHO study sites. 
4.0 
8 
Revised definition to use irRECIST 
response criteria 
Definition of immune response was 
amended from irRC to irRECIST to 
facilitate unidimensional measure of 
tumor response 
5.0 
Synopsis 
Study Center: multicenter [U.S. 
Only] 
Synopsis updated to reflect the study is 
multi-center 
5.0 
4.4.1.2 
Multicenter Registration 
Instructions for multicenter study 
registrations added 
5.0 
5.1.1.1, 5.2.1.1 
Multicenter Acquisition 
Instructions for multicenter study drug 
acquisition added 
6.0 
Synopsis, 
schema, 3.1, 
6.1, 6.1.1, 6.4, 
7.1.3 
Initial treatment with olaparib 
monotherapy shortened from 4 
weeks to 2 weeks 
The treatment timeframe with olaparib 
monotherapy is reduced to better 
assess biological activity of study drug. 
The shortened timeframe also 
decreases the time to which participants 
can receive the combination of olaparib 
and durvalumab. 
6.0 
3.1, 7.4.1, 
7.4.1.2, 7.1.3 
Biopsy pre- and post- olaparib 
monotherapy reduced from 4 weeks 
to 2 weeks 
Change in schedule is made to align 
with revised treatment period for 
olaparib monotherapy 
6.0 
4.1 
Inclusion criteria revised to clarify  
prior anti- PD-1 or PD-L1 therapy is 
not allowed in the metastatic 
setting. Additional allowance for 
patients that received prior 
immunotherapy in the adjuvant 
Changes to study eligibility made to 
reflect real-world experience with this 
patient population. 

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
4 
# 
Section 
Change 
Justification 
setting.  
6.0 
4.2 
Reduced washout period from 28 
days to 14 days  
Changes to study eligibility made to 
reflect real-world experience with this 
patient population in that study agents 
can be safely initiated after this 14 day 
period. 
6.0 
4.3.1 
Table 2 deleted 
Projected accrual table removed as 
study is now multisite with subsites in 
OR, WA, and MN 
6.0 
7.2 
Imaging revised to allow for CT, 
MRI, PET, or PET/CT 
Changes to study eligibility made to 
reflect real-world experience with this 
patient population. 
6.0 
7.4 
Revised tissue collection and 
processing 
Revised for clarity 
6.0 
7.5 
Updated GeneTrails Panel 
Revised to reflect updated versioning of 
panel being utilized in OHSU site 
laboratory  
7.0 
Synopsis, 3.1, 
6.1.1, 6.4 
Lead-in treatment with olaparib 
monotherapy is increased from 14-
days to 28-days 
 
7.0 
Appendix C 
Revised contraception requirement 
to 2 months 
Revised to align with inclusion criteria 
requirement of 60 days.  
7.0 
7.4.3 
Fecal sample collection is optional 
Revised for clarity 
7.0 
7.1.7 
Corrected “RT” to study therapy 
with regards to AE assessment 
Correction of typographical error 
7.0 
7.7 
Revised statement to denote what 
information is required for collection 
from individuals who are screen 
failures. 
Revised for clarity 
7.0 
9.5 
Corrected AE causality rating from 
“yes or no” to “definite, probable, 
unrelated.” 
Correction of typographical error 
7.0 
9.5 
Revised AE follow-up period to 
include last dose of study drug and 
not last day of study participation  
Revised for clarity 
7.0 
9.5.1 
Replaced durvalumab with study 
drug 
Corrected typographical error to denote 
that there is more than one study drug  
7.0 
9.7.3 
Revised consenting of participant’s 
whose sexual partner becomes 
pregnant  
Corrected an incomplete statement. 
7.0 
10.1, 10.2.3.3 
Revised requirements for 
conducting interim analysis to clarify 
that only 1 post-baseline disease 
assessment to conduct interim 
analysis 
Revised for clarity 
8.0 
Synopsis, 3.1.1 
3.2.1, 3.2.2 
End timing of efficacy assessment 
(ORR, CBR, DOR) revised to End 
of treatment (previously 6 months 
post-treatment) 
Revisions made to ensure clarity and 
consistency across protocol.  

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
5 
# 
Section 
Change 
Justification 
8.0 
8.3.3 
Objective response rate description 
corrected to include definition of 
assessment 
Defintion corrected for accuracy to align 
with statistical analysis of ORR being 
assessed as the best overall response 
9.0 
The modifications in this version 9 of the protocol includes the addition of 3 new treatment arms. 
Following 28-day monotherapy with olaparib, a participant’s tumor will be characterized using 
several clinically-validated assays, the results of which will be used to guide a treatment 
assignment comprising of olaparib in combination with durvalumab (Arm 1), capivasertib (Arm 2), 
or selumetinib (Arm 3), or ceralasertib monotherapy (Arm 4). The modifications included in this 
amendement detail the background and rationale for the addition of these investigational 
products to the study, along with justification to the changes in study design approach. Changes 
reflected in this amendment include the dosing guidelines and toxicity management for 
capivasertib, selumetinib, and ceralasertib, respectively, as well as requirements for drug-
specific assessments, and known toxicities and adverse events for each drug agent.  Changes to 
the study design and the statistical approach have also been added to Section 10. A description 
of the criteria guiding the decision logic for treatment arm assignment is provided in Section 3, 
and Appendix A. The total sample size for the revised study is increased up to n = 132. 
9.1 
Cover page, 
Header 
PI Change 
PI Change 
9.2 
Cover page, 
Header 
PI Change 
PI Change 
 
 

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
6 
SYNOPSIS 
 
Study Title 
A Phase II, Open-Label, Study of Olaparib in combination with either  
Durvalumab (MEDI4736), Selumetinib, or Capivasertib, or Ceralasertib 
monotherapy in Patients with Metastatic Triple-Negative Breast Cancer 
Protocol # 18504 
Study Center multicenter [U.S. only]   
Clinical Phase Phase II - Combination 
Investigational 
Components  
Olaparib - FDA Approved Drug - used for an unapproved purpose 
Durvalumab - FDA Approved Drug - used for an unapproved purpose 
Capivasertib - Investigational Drug 
Selumetinib - FDA Approved Drug - used for an unapproved purpose 
Ceralasertib - Investigational Drug 
Interventional Study Type Multi-arm 
Précis 
 
This is an open-label, non-comparative, multi-arm, Phase II study to 
assess the efficacy of combining olaparib with durvalumab (MEDI4736), 
capivasertib, or selumetinib, or ceralasertib monotherapy in the 
treatment of patients with metastatic triple-negative breast cancer 
(TNBC).  All eligible participants with biopsy-proven TNBC will undergo 
a pre-treatment biopsy, after which they will receive a 28 (± 7) -day, 
single cycle, induction treatment of olaparib (300 mg, PO BID).  At the 2 
week mark, participants will then undergo a repeat on-treatment biopsy. 
After Cycle 1, participants will be assigned to receive olaparib as part of 
4 potential treatment arms: olaparib and durvalumab (Arm 1), olaparib 
and selumetinib (Arm 2), olaparib and capivasertib (Arm 3), and 
ceralasertib monotherapy (Arm 4). Assignment to a study arm uses a 
decision-tree logic that is based on predefined molecular characteristics 
of the participant’s tumor at baseline or following olaparib monotherapy. 
Combination therapy in each treatment arm will continue for 12 cycles 
until disease progression, unacceptable toxicity, or participant 
withdrawal, whichever occurs first. Participants will also be offered 
optional repeat biopsy on progression. This is a non-comparative study, 
and the efficacy and safety of the assigned study interventions for each 
treatment arm (i.e., Arm 1, Arm 2, Arm 3, or Arm 4) will be evaluated 
independently of one another. The primary endpoint of this study is to 
determine the overall response rate (ORR) for olaparib in combination 
with durvalumab, capivasertib, or selumetinib, or ceralasertib 
monotherapy.  Secondary endpoints of efficacy measures include: 
clinical benefit rate (CBR), duration of response (DOR), progression-
free survival (PFS), and overall survival (OS),). Safety and tolerability of 
each proposed treatment arm will also be evaluated. Participant 
research tissue samples will be subject to comprehensive multi-omics, 
and an exploratory-based approach to evaluate predictive biomarkers 
of resistance to therapy and disease progression.  
 
Primary Objectives Assess the overall response to treatment  

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
7 
Secondary Objectives 
1. Assess participant benefit from treatment 
2. Determine the time to disease progression following response to 
study therapy 
3. Determine time to first disease progression or death of participants 
enrolled on the study 
4. Determine survival of participants enrolled on the study  
5. Assess safety and tolerability of the proposed therapy 
Exploratory Objectives 
1. To assess a change in quality of life (QOL) measured by QLQC30 
in each treatment arm. 
2. To assess a change in QOL measured by QLQBR23 in each 
treatment arm.  
3. Examine response rates depending on tumor characteristics  
4. Identify predictive biomarkers of sensitivity to therapy  
5. Identify emerging mechanism of resistance to therapy  
6. Determine changes in tumor cells induced by PARP inhibitors 
7. Identify predictive biomarkers to select  combinatorial therapy that 
could overcome resistance to therapy  
Primary Endpoints 
1. ORR for olaparib combined with durvalumab (Arm 1) 
2. ORR for olaparib combined with selumetinib (Arm 2) 
3. ORR for olaparib combined with capivasertib (Arm 3) 
4. ORR for ceralasertib (Arm 4) 
Secondary Endpoints 
1. CBR for each treatment Arm. 
2. DOR for each treatment Arm.  
3. PFS for each treatment Arm. 
4. OS for each treatment Arm. 
5. Incidence of ≥Grade 3 toxicities (per CTCAE 5.0) for each  
treatment arm 
Exploratory Endpoints 1. Change From Baseline to end of treatment in EORTC QLQ-C30  
2. Change From Baseline to end of treatment in EORTC QLQBR23 
 
Number of Participants Up to N=132 
Duration of Therapy 
Participants are planned to receive 13 cycles of therapy (approximately 
52 weeks). Participants deriving clinical benefit from assigned treatment 
may, at the investigator's discretion and in the absence of disease 
progression or unacceptable toxicity, continue on therapy beyond the 
planned 13 cycles 
Duration of Follow Up 12 months  
Key Inclusion Criteria 
• 
Participants with biopsy-proven metastatic TNBC defined as 
ER<10%, PR<10%, HER2 non-amplified by CAP guidelines. 
o 
Individuals with tumors showing androgen receptor (AR) ≥80% 
by immunohistochemistry are excluded from study participation.  
• 
Participants must have at least one measurable site of disease as 
defined by RECIST v1.1 that is amenable to biopsy.   
• 
Participants with or without germline BRCA mutated TNBC are 
eligible for study treatment. 
• 
Participants who have not received any prior systemic therapy for 
metastatic disease are eligible 
• 
≤2 chemotherapy allowed in the metastatic setting,  
• 
ECOG PS ≤1,  

An Adaptive Multidrug Treatment of Evolving Cancers Trial in Triple Negative Breast Cancer  
Protocol # 18504 
Version 9.2 
10 Apr 2023 
PI: Alexandra Zimmer, MD, MSc 
 
8 
• 
No prior PARP inhibitor exposure in the metastatic setting, and prior 
treatment related toxicities resolved to ≤Grade 1.  
Key Exclusion Criteria 
• 
Known active autoimmune disease requiring steroid therapy or 
disease-modifying agents (Arm 1 only) 
• 
Uncontrolled Human Immunodeficiency Virus (HIV).  Controlled 
HIV, defined as basal CD4+ T-cell count ≥200 cells/mm3 and low-
level viremia (< 60 copies/ml) is permitted. 
• 
Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected). 
• 
Symptomatic brain metastases  
• 
Arm-specific exclusion criteria as described in protocol. 
 
Statistical Considerations 
Arm 1: A two-stage analysis will be performed using a Simon 2-stage 
Minimax design. The null (Immune checkpoint blockade alone) and 
alternative (Durvalumab and Olaparib) hypotheses are: H0: π = .15 and 
Ha: π =.35. For the primary endpoint, a total sample size of 28 
participants will achieve 80 percent power to detect the overall 
response rate difference of 0.20 using the two-stage Minimax design 
with one-sided type I error = 0.05. The trial will be terminated in stage I 
if 2 or less out of the first 15 participants respond. If the trial goes on to 
the stage 2, a total of 28 participants will be studied. If the total number 
responding is less than or equal to 7, the drug is rejected.  
 
Arms 2-4:  Fleming’s two-stage design will be used. The null (PARPi 
monotherapy) and alternative (olaparib and capivasertib, selumetinib, 
or capivasertib) hypotheses are: H0: π = 0.15 and Ha: π = 0.40. For the 
primary endpoint, a total sample size of 22 participants will achieve 80 
percent power to detect the overall response rate difference of 0.25 
with one-sided type I error=0.05. In the first stage, 11 patients will be 
accrued. If there are 1 or fewer responses in these 11 participants, the 
study will be terminated in stage 1. Otherwise, 11 additional participants 
will be accrued for a total of 22. The null hypothesis will be rejected if 7 
or more responses are observed in 22 participants. If there are 5 or 
more responses in 11 participants, the arm will open for an expansion 
study with biomarker negative patients.  
 
Expansion for biomarker negative (Arms 2 & 3 only): A two-stage 
analysis will be performed using a Simon 2-stage Minimax design. The 
null (PARPi monotherapy) and alternative hypotheses are: H0: π = 0.15 
and Ha: π = 0.4.  For the primary endpoint, a total sample size of 19 
participants will achieve 80 percent power to detect the overall 
response rate difference of 0.25 using the two-stage Minimax design 
with one-sided type I error =0.05. The trial arm will be terminated in 
stage I if 1 or less out of the first 9 participants respond. If the trial arm 
goes on to stage 2, a total of 19 participants will be studied. The null 
hypothesis will be rejected if more than 5 responses are observed in 19 
participants. 
Efficacy Assessments  Overall response rate, Clinical Benefit Rate, Duration of Response, 
Progression-free survival, Overall survival  
Safety Assessments  Adverse events will be collected and graded according to CTCAE 5.0 

 
9 
 
SCHEMATIC OF STUDY DESIGN  
 
This is multi-arm, open-label, Phase II study to assess the efficacy of combining olaparib with durvalumab, selumetinib, or capivasertib, or ceralasertib 
monotherapy to treat patients with metastatic triple negative breast cancer (TNBC).  This study will enroll participants with metastatic TNBC, defined as ER < 10%, 
PR < 10%, HER-2 non-amplified, and AR <80%.  Eligible participants that consent to study will undergo a pre-treatment biopsy, following which patients will 
proceed to receive a single cycle (i.e., 28 days ±7days) of olaparib (300 mg, PO, BID). After 14 days of receiving olaparib monotherapy, participants will undergo a 
second on-treatment biopsy (Cycle 1, Day 14 [±7 days]). After completing the single cycle of olaparib monotherapy, participants will be assigned to one of four 
treatment arms based on predefined molecular tumor characteristics indentified pre- or post-treatment with olaparib monotherapy.  Each treatment arm consists of 
participants receiving olaparib (300 mg BID) in combination with durvalumab (1500 mg, IV, q4week), selumetinib (BSA dosing per Table 15), or capivasertib (400 
mg BID, 4 days on/3 days off), or ceralasertib monotherapy (240 mg BD days 1-14 of each cycle). Participants are planned to receive their assigned combination 
treatment for a total of 12 cycles.  At the completion of all on-study procedures, participants will be considered off-treatment and be followed-up for disease and 
survival outcomes.  Participants will be asked to submit an optional tumor biopsy in the event of disease progression.  This a non-comparitive study, and each 
treatment arm will be independently evaluated.  The primary endpoint is objective response rate following completion of assigned study therapy. Additional 
efficacy endpoints will be evaluated by assessing clinical benefit rate, duration of response, and survival. Safety of the on-study olaparib combination treatment 
arms and ceralasertib monotherapy will also be assessed. Exploratory research using patient biopsies that are sequentially collected will investigate the cellular 
and molecular biology of tumor cells to better understand emerging mechanisms of resistance to therapy.     

 
10 
 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... 1 
SYNOPSIS ................................................................................................................................. 6 
SCHEMATIC OF STUDY DESIGN ............................................................................................. 9 
TABLE OF CONTENTS ................................................... ERROR! BOOKMARK NOT DEFINED. 
LIST OF TABLES ..................................................................................................................... 21 
LIST OF FIGURES ................................................................................................................... 22 
LIST OF ABBREVIATIONS ...................................................................................................... 23 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 25 
 
Breast cancer epidemiology ...................................................................................... 25 
 
TNBC ........................................................................................................................ 25 
1.2.1 PARP Inhibitors in BRCA Associated Breast Cancer ............................................ 25 
 
Immunotherapies ...................................................................................................... 27 
1.3.1 Immune Checkpoint Blockade in TNBC................................................................ 28 
1.3.2 Durvalumab background/non-clinical and clinical experience ............................... 29 
1.3.3 Rationale for DURVALUMAB fixed dosing ........................................................... 29 
1.4 
Phosphoinositide 3 (PI3)-kinase and AKT signaling in TNBC .................................... 30 
1.4.1 Combined Inhibition of PI3K signaling and PARP ................................................. 30 
1.4.1.1 
AKT inhibitor - Capivasertib (AZD5363) ............................................... 31 
1.5 
RAS-Raf-MEK-ERK Signaling in TNBC .................................................................... 32 
1.5.1 Combined inhibition of PARP and Raf-MEK-ERK signaling .................................. 33 
1.5.1.1 
MEK inhibitor - Selumetinib (AZD6244) ................................................ 33 
1.6 
Ataxia telangiectasia and Rad3-related protein (ATR) SignALing in TNBC ............... 34 
1.6.1.1 
ATR inhibitor - Ceralasertib (AZD6738) ................................................ 36 
 
Rationale .................................................................................................................. 37 
1.7.1 Targeting PARP and the immune response ......................................................... 38 
1.7.2 Combined Targeting of PARP and capivasertib .................................................... 38 
1.7.3 Combined Targeting of PARP and Selumetinib .................................................... 38 
1.7.4 ATR Targeting by Ceralasertib ............................................................................. 39 
 
Exploratory Studies Background ............................................................................... 39 
1.8.1 Pre-treatment biopsy: ........................................................................................... 39 
1.8.2 On-treatment biopsy: ............................................................................................ 39 
1.8.3 Post-progression biopsy: ...................................................................................... 40 

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1.8.4 Cellular and Molecular Profiling of serial biopsies ................................................. 40 
 
Potential Risks and Benefits ..................................................................................... 40 
1.9.1 Known Potential Risks .......................................................................................... 40 
1.9.1.1 
Immune checkpoint blockade ............................................................... 40 
1.9.1.2 
Capivasertib ......................................................................................... 41 
1.9.1.3 
Selumetinib .......................................................................................... 41 
1.9.1.4 
Ceralasertib.......................................................................................... 41 
1.9.2 Known Potential Benefits ..................................................................................... 41 
2. OBJECTIVES ...................................................................................................................... 43 
 
Primary Objectives .................................................................................................... 43 
 
Secondary Objectives ............................................................................................... 43 
 
Exploratory Objectives .............................................................................................. 43 
3. STUDY DESIGN AND ENDPOINTS .................................................................................... 44 
 
Description of the Study Design ................................................................................ 44 
3.1.1 Scientific Rationale for Study Design .................................................................... 46 
 
Study Endpoints ........................................................................................................ 48 
3.2.1 Primary Endpoint .................................................................................................. 48 
3.2.2 Secondary Endpoints ........................................................................................... 48 
3.2.3 Exploratory Endpoints .......................................................................................... 49 
4. STUDY ENROLLMENT AND WITHDRAWAL ..................................................................... 50 
 
Participant Inclusion Criteria ..................................................................................... 50 
 
Participant Exclusion Criteria .................................................................................... 51 
4.2.1 Drug-specific exclusion criteria ............................................................................. 53 
4.2.1.1 
Durvalumab Exclusion Criteria (if being considered for Arm 1) ............. 54 
4.2.1.2 
Selumetinib Exclusion Criteria (if being considered for Arm 2) ............. 55 
4.2.1.3 
Capivasertib Exclusion Criteria (if being considered for Arm 3) ............ 56 
4.2.1.4 
Ceralasertib Exclusion Criteria (if being considered for Arm 4) ............. 58 
 
Strategies for Recruitment and Retention ................................................................. 59 
4.3.1 Accrual Estimates ................................................................................................ 60 
4.3.2 Inclusion of Children ............................................................................................. 60 
 
Registration Procedures ........................................................................................... 60 
4.4.1 Participant Registration ........................................................................................ 60 
4.4.1.1 
Local Registration ................................................................................ 60 
4.4.1.2 
Multicenter Registration ....................................................................... 60 
 
Participant Screening and Enrollment ....................................................................... 61 
 
Participant Withdrawal or Discontinuation ................................................................. 61 
4.6.1 Handling Participant Withdrawal and Discontinuation ........................................... 62 

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Off-Study Criteria ...................................................................................................... 62 
4.7.1 Screen Failures .................................................................................................... 62 
 
Study Discontinuation ............................................................................................... 62 
5. INVESTIGATIONAL PRODUCT .......................................................................................... 64 
 
Olaparib .................................................................................................................... 64 
5.1.1 Acquisition ............................................................................................................ 64 
5.1.1.1 
Multicenter Acquisition ......................................................................... 64 
5.1.2 Formulation, Appearance, Packaging, and LABELING ......................................... 64 
5.1.3 Product Storage and Stability ............................................................................... 64 
5.1.4 Compatibility ........................................................................................................ 64 
5.1.5 Handling ............................................................................................................... 65 
5.1.6 Preparation .......................................................................................................... 65 
5.1.7 Administration ...................................................................................................... 65 
5.1.8 Special Considerations for Administration ............................................................ 65 
 
Durvalumab (MEDI4736) .......................................................................................... 65 
5.2.1 Acquisition ............................................................................................................ 65 
5.2.1.1 
Multicenter Acquisition ......................................................................... 65 
5.2.2 Formulation, Appearance, Packaging, and Labeling............................................. 66 
5.2.3 Compatibility ........................................................................................................ 66 
5.2.4 Handling ............................................................................................................... 66 
5.2.5 Preparation of Durvalumab doses for administration with an iv bag ...................... 66 
5.2.6 Administration ...................................................................................................... 66 
5.2.7 Special Consideration for Administration .............................................................. 67 
5.2.7.1 
Monitoring Durvalumab Dose Administration ........................................ 67 
 
Capivasertib .............................................................................................................. 67 
5.3.1 Acquisition ............................................................................................................ 67 
5.3.1.1 
Multicenter Acquisition ......................................................................... 67 
5.3.2 Formulation, Appearance, Packaging, and LABELING ......................................... 68 
5.3.3 Product Storage and Stability ............................................................................... 68 
5.3.4 Handling ............................................................................................................... 68 
5.3.5 Preparation .......................................................................................................... 68 
5.3.6 Administration ...................................................................................................... 68 
5.3.7 Special Considerations for Administration ............................................................ 68 
 
Selumetinib ............................................................................................................... 68 
5.4.1 Acquisition ............................................................................................................ 68 

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5.4.1.1 
Multicenter Acquisition ......................................................................... 69 
5.4.2 Formulation, Appearance, Packaging, and LABELING ......................................... 69 
5.4.3 Product Storage and Stability ............................................................................... 69 
5.4.4 Handling ............................................................................................................... 69 
5.4.5 Preparation .......................................................................................................... 69 
5.4.6 Administration ...................................................................................................... 69 
5.4.7 Special Considerations for Administration ............................................................ 69 
 
Ceralasertib .............................................................................................................. 70 
5.5.1 Acquisition ............................................................................................................ 70 
5.5.1.1 
Multicenter Acquisition ......................................................................... 70 
5.5.2 Formulation, Appearance, Packaging, and LABELING ......................................... 70 
5.5.3 Product Storage and Stability ............................................................................... 70 
5.5.4 Compatibility ........................................................................................................ 70 
5.5.5 Handling ............................................................................................................... 70 
5.5.6 Preparation .......................................................................................................... 71 
5.5.7 Administration ...................................................................................................... 71 
5.5.8 Special Considerations for Administration ............................................................ 71 
 
Accountability (All investigational Products) .............................................................. 71 
 
Destruction and Return (All Investigational Products) ............................................... 72 
6. TREATMENT PLAN............................................................................................................. 73 
 
Dosage and Administration ....................................................................................... 73 
6.1.1 Cycle 1 – Lead in monotherapy Regimen ............................................................. 73 
6.1.2 Cycle 2 to Cycle 13 – Combination Therapies AND CERALASERTIB 
MONOTHERAPY ............................................................................................ 73 
6.1.2.1 
Arm 1 – Olaparib and Durvalumab ....................................................... 73 
6.1.2.2 
Arm 2 – Olaparib and Selumetinib ........................................................ 73 
6.1.2.3 
Arm 3 – Olaparib and Capivasertib ...................................................... 74 
6.1.2.4 
Arm 4 – Ceralasertib monotherapy ....................................................... 74 
 
Dosing Delays ........................................................................................................... 74 
6.2.1 Olaparib ............................................................................................................... 74 
6.2.2 Durvalumab .......................................................................................................... 74 
6.2.3 Capivasertib ......................................................................................................... 74 
6.2.4 Selumetinib .......................................................................................................... 75 
6.2.5 Ceralasertib .......................................................................................................... 75 
 
Dose Modification Guidelines .................................................................................... 75 
6.3.1 Management of Olaparib-Related Toxicities ......................................................... 75 

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6.3.1.1 
Management of hematological toxicity – Anemia .................................. 76 
6.3.1.2 
Management of hematological toxicity – neutropenia, leukopenia 
and thrombocytopenia .......................................................................... 77 
6.3.1.3 
Management of prolonged hematological toxicities .............................. 77 
6.3.1.4 
Management of non-hematological toxicity .......................................... 78 
6.3.1.5 
Management of new or worsening pulmonary symptoms ..................... 78 
6.3.1.6 
Management of Nausea and Vomiting ................................................. 78 
6.3.1.7 
Interruptions for intercurrent non-toxicity related events ....................... 78 
6.3.2 Renal Impairment ................................................................................................. 79 
6.3.3 Management of Durvalumab-Related Toxicities ................................................... 79 
6.3.3.1 
Infusion-related reaction ....................................................................... 80 
6.3.4 Management of Capivasertib-Related Toxicities ................................................... 81 
6.3.4.1 
Dose Modifications due to general capivasertib-related toxicities ......... 81 
6.3.4.2 
Hyperglycemia ..................................................................................... 82 
6.3.4.3 
Use of metformin .................................................................................. 83 
6.3.4.4 
Maculo-papular rash ............................................................................ 84 
6.3.4.5 
Hypersensitivity .................................................................................... 84 
6.3.4.6 
Diarrhea ............................................................................................... 85 
6.3.5 Management of Selumetinib-Related Toxicities .................................................... 86 
6.3.5.1 
Diarrhea ............................................................................................... 87 
6.3.5.2 
Visual Disturbances ............................................................................. 88 
6.3.5.3 
Rash .................................................................................................... 89 
6.3.5.4 
Paronychia ........................................................................................... 90 
6.3.5.5 
Oral Mucositis ...................................................................................... 90 
6.3.5.6 
Creatine Kinase (CK) Elevation ............................................................ 91 
6.3.5.7 
Dyspnea ............................................................................................... 92 
6.3.5.8 
Left Ventricular Ejection Fraction (LVEF) Reduction or 
Dysfunction .......................................................................................... 93 
6.3.6 Management of Ceralasertib-Related Toxicities ................................................... 93 
6.3.6.1 
Dose reductions for Ceralasertib monotherapy .................................... 94 
6.3.6.2 
Individual stopping criteria .................................................................... 96 
6.3.6.2.1. 
Hepatic ................................................................................................. 96 
6.3.6.2.2. 
Cardiovascular ..................................................................................... 96 
6.3.6.3 
Ceralasertib as CYP3A drug substrate ................................................. 96 
6.3.6.4 
Ceralasertib as Pgp drug substrate ...................................................... 97 
6.3.6.5 
Ceralasertib as Pgp drug substrate ...................................................... 97 
 
Treatment Period and Maintenance .......................................................................... 97 
 
Concomitant Medication and Supportive Care Guidelines ........................................ 97 
6.5.1 Pneumonitis ......................................................................................................... 97 
6.5.2 Diarrhea/Colitis ..................................................................................................... 98 
6.5.3 Nausea/vomiting .................................................................................................. 98 
6.5.4 Anemia ................................................................................................................. 98 
6.5.5 Thrombocytopenia ............................................................................................... 99 

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6.5.6 Diabetes Mellitus .................................................................................................. 99 
6.5.7 Hypophysitis / Adrenal Insufficiency ..................................................................... 99 
6.5.8 Hyperthyroidism or Hypothyroidism ...................................................................... 99 
6.5.9 Hyperphosphatemia ............................................................................................. 99 
6.5.10 
Hepatic Adverse Events .................................................................................. 99 
6.5.11 
Nephritis And Renal Failure ........................................................................... 100 
6.5.12 
Infection Prophylaxis...................................................................................... 100 
6.5.13 
Immune-Related and/or Hypersensitivity Reactions ....................................... 100 
6.5.14 
Diet ................................................................................................................ 100 
6.5.15 
Blood Donation .............................................................................................. 100 
6.5.16 
Dermatological Care ...................................................................................... 101 
6.5.17 
Visual Function .............................................................................................. 101 
6.5.18 
Contraception ................................................................................................ 101 
6.5.19 
Use in Pregnancy .......................................................................................... 102 
6.5.20 
Use in Nursing Women .................................................................................. 102 
 
Precautionary Medications, Treatments, and Procedures ....................................... 102 
6.6.1 Olaparib ............................................................................................................. 102 
6.6.2 Durvalumab ........................................................................................................ 105 
6.6.3 Capivasertib ....................................................................................................... 106 
6.6.3.1 
Drugs that may influence capivasertib pharmacokinetics ................... 106 
6.6.3.2 
Drugs that may be influenced by capivasertib .................................... 108 
6.6.3.3 
Capivasertib Precautions Regarding QTc-prolongation 
Medications ........................................................................................ 109 
6.6.4 Selumetinib ........................................................................................................ 110 
6.6.4.1 
Selumetinib Precautions Regarding CYP-interacting Medication ........ 110 
6.6.4.2 
Vitamin E intake ................................................................................. 110 
6.6.4.3 
Oral Hygeine ...................................................................................... 110 
6.6.5 Ceralasertib ........................................................................................................ 110 
6.6.5.1 
Ceralasertib Precautions Regarding CYP-interacting Medication ....... 111 
6.6.5.2 
Ceralasertib Precautions Regarding Pgp inhibitors/inducers 
and/or BCRP inhibitors ....................................................................... 111 
6.6.5.3 
Ceralasertib Precautions Regarding OATP1B1 and BCRP 
Substrates .......................................................................................... 111 
 
Prohibited Medications, Treatments, and Procedures ............................................. 111 
7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE .............................................. 113 
 
Study Specific Procedures ...................................................................................... 113 
7.1.1 Medical history ................................................................................................... 113 
7.1.2 Disease Assessment .......................................................................................... 113 

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7.1.3 Medication history .............................................................................................. 113 
7.1.4 Physical examination .......................................................................................... 113 
7.1.4.1 
Vital signs .......................................................................................... 113 
7.1.4.2 
Height and weight .............................................................................. 113 
7.1.4.3 
Performance status ............................................................................ 113 
7.1.5 Electrocardiogram (ECG) ................................................................................... 114 
7.1.5.1 
Selumetinib arm (only) ....................................................................... 114 
7.1.5.2 
Capivasertib arm (only) ...................................................................... 114 
7.1.6 Echocardiogram (ECHO)/Multi-gated acquisition (MUGA) Scan ........................ 114 
7.1.7 Medical Diary ..................................................................................................... 114 
7.1.8 Adverse event evaluation ................................................................................... 115 
7.1.9 Eye examination (Selumetinib Treatment Arm Only) .......................................... 115 
 
Radiographic or other imaging assessments .......................................................... 115 
7.2.1 Computed Tomography ...................................................................................... 116 
7.2.2 MRI .................................................................................................................... 116 
7.2.3 Bone Scans ........................................................................................................ 116 
7.2.3.1 
Dose administration ........................................................................... 116 
7.2.3.2 
Imaging parameters ........................................................................... 116 
7.2.4 Positron Emission Tomography (PET)................................................................ 116 
7.2.4.1 
Participant Guidelines ........................................................................ 116 
7.2.4.2 
Imaging Technique............................................................................. 117 
7.2.4.3 
Study Processing ............................................................................... 117 
 
Laboratory Procedures and Evaluations ................................................................. 118 
7.3.1 Hematology ........................................................................................................ 118 
7.3.2 Biochemistry ...................................................................................................... 118 
7.3.3 Tumor markers ................................................................................................... 119 
7.3.4 Urinalysis ........................................................................................................... 119 
7.3.5 Coagulation panel .............................................................................................. 119 
7.3.6 Pregnancy test ................................................................................................... 119 
7.3.7 Bone marrow or blood cytogenetic samples ....................................................... 119 
 
Biospecimen collection ........................................................................................... 120 
7.4.1 Tissue Biopsy ..................................................................................................... 120 
7.4.1.1 
Pre-treatment biopsy .......................................................................... 120 
7.4.1.2 
On-treatment Biopsy .......................................................................... 120 
7.4.1.3 
Optional core biopsy at disease progression ...................................... 121 
7.4.2 Blood Collection For research ............................................................................ 121 
7.4.2.1 
Blood for Clinical Analysis .................................................................. 121 
7.4.2.2 
Blood for Research Analytics ............................................................. 121 

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7.4.3 Fecal Sample Collection ..................................................................................... 121 
 
SMMART Clinical Analytics Platform ...................................................................... 122 
7.5.1 Immunohistochemistry ....................................................................................... 122 
7.5.2 Targeted DNA Sequencing................................................................................. 122 
7.5.3 Whole Exosome Sequencing ............................................................................. 122 
7.5.4 RNA Sequencing ................................................................................................ 123 
7.5.5 Protein Profiling .................................................................................................. 123 
 
SMMART Exploratory Research Analytics Platform ................................................ 123 
 
Quality of Life (QOL) and Patient-reported Outcomes (PRO) .................................. 123 
 
Screening Assessments ......................................................................................... 124 
 
Baseline Assessments ............................................................................................ 124 
 Assessments During Treatment .............................................................................. 124 
 Early Termination or End of Treatment Visit ............................................................ 125 
 Follow-up ................................................................................................................ 125 
 Unscheduled Visits ................................................................................................. 125 
 Schedule of Events ................................................................................................. 126 
8. EFFICACY MEASURES .................................................................................................... 129 
 
Definition of Efficacy Measures ............................................................................... 129 
8.1.1 Disease Parameters ........................................................................................... 129 
 
Disease Evaluation ................................................................................................. 130 
 
Efficacy Criteria for Tumor Response ..................................................................... 130 
8.3.1 Evaluation of Target Lesion ................................................................................ 130 
8.3.2 Evaluation of Non-Target Lesion ........................................................................ 131 
8.3.2.1 
Evaluation of New Lesions ................................................................. 131 
8.3.3 Objective response Rate .................................................................................... 131 
8.3.4 Clinical Benefit Rate ........................................................................................... 132 
8.3.5 Duration of Response ......................................................................................... 132 
8.3.6 Progression-Free Survival .................................................................................. 132 
8.3.7 Overall Survival .................................................................................................. 133 
 
Response Review ................................................................................................... 133 
 
Definition of Tumor Response Using immune related response Criteria (irRC) ....... 133 
8.5.1 Definition of index Lesion Response Using irRECIST ......................................... 133 
8.5.2 Impact of New Lesions on irRECIST .................................................................. 134 
9. SAFETY ............................................................................................................................. 135 
 
Specification Of Safety Parameters ........................................................................ 135 

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Definitions ............................................................................................................... 135 
9.2.1 Adverse Event (AE) ............................................................................................ 135 
9.2.2 Serious Adverse Event (SAE) ............................................................................ 135 
9.2.2.1 
New Malignancies On-study ............................................................... 136 
9.2.3 Unanticipated Problems (UP) ............................................................................. 136 
9.2.4 Severity of Event ................................................................................................ 136 
9.2.5 Assessment of Causality Relationship To Study Agent ...................................... 137 
 
Expectedness ......................................................................................................... 137 
 
Adverse Event List(s) .............................................................................................. 137 
9.4.1 Adverse Event List for Olaparib .......................................................................... 137 
 
Olaparib Adverse Events of ......................................................................... 137 
9.4.1.1 
Special Interest (AESI) ....................................................................... 137 
9.4.2 Adverse Event List for Durvalumab .................................................................... 138 
9.4.2.1 
Durvalumab Adverse Events of Special Interest ................................. 138 
9.4.3 Adverse events list for capivasertib .................................................................... 139 
9.4.3.1 
Capivasertib Adverse Events of Special Interest ................................ 139 
9.4.4 Adverse Events List For Selumetinib .................................................................. 139 
9.4.4.1 
Selumetinib Adverse Events of Special Interest ................................. 140 
9.4.5 Adverse Events List For Ceralasertib ................................................................. 141 
 
Adverse Event Assessment and Follow-Up ............................................................ 141 
9.5.1 Adverse events after the 90 day follow-up period ............................................... 142 
 
Overdose ................................................................................................................ 142 
9.6.1 Olaparib, Selumetinib, Capivasertib, and Ceralasertib ........................................ 142 
9.6.2 Durvalumab ........................................................................................................ 143 
 
Reporting Procedures ............................................................................................. 143 
9.7.1 OHSU IRB Reporting of Unanticipated Problems and Adverse Events .............. 143 
9.7.2 MedWatch Reporting .......................................................................................... 144 
9.7.3 Reporting Of Pregnancy ..................................................................................... 144 
 
Reporting of Deaths to AstraZeneca ....................................................................... 145 
 
Study Stopping Rules ............................................................................................. 145 
10. STATISTICAL CONSIDERATIONS ................................................................................ 146 
 Analysis Populations ............................................................................................... 146 
 Description of Statistical Methods ........................................................................... 146 
10.2.1 
General Approach ......................................................................................... 146 
10.2.2 
Analysis of Primary Endpoint(s) ..................................................................... 146 

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10.2.3 
Analysis Of The Secondary Endpoint(S) ........................................................ 146 
10.2.3.1 
Safety Endpoint .................................................................................. 146 
10.2.3.2 
Efficacy Endpoints.............................................................................. 146 
10.2.3.3 
Interim Analysis and Stopping Rules – Arm 1 (olaparib and 
durvalumab) ....................................................................................... 147 
10.2.3.4 
Interim Analysis and Stopping Rules – Arm (olaparib in 
combination with selumetinib or capivasertib, or ceralasertib  
monotherapy) ..................................................................................... 147 
10.2.3.5 
Biomarker Negative Expansion Cohort (Arms 2 and 3 only) ............... 147 
10.2.4 
Analysis of Exploratory Endpoints.................................................................. 147 
10.2.4.1 
Analysis of Quality of Life Measures .................................................. 148 
10.2.4.2 
Additional Analyses ............................................................................ 148 
 Sample Size, Power, Accrual Rate, and Study Duration ......................................... 148 
10.3.1 
Sample size and Power ................................................................................. 148 
10.3.1.1 
Arm 1 (olaparib and durvalumab) ....................................................... 148 
10.3.1.2 
Arms 2-4 (olaparib and selumetinib, or capivasertib, or 
ceralasertib monotherapy) .................................................................. 149 
 Handling of Missing Data ........................................................................................ 149 
11. CLINICAL MONITORING ................................................................................................ 150 
 OHSU Knight Cancer Institute Data & Safety Monitoring Plan (DSMP) ................... 150 
 Clinical Data & Safety Monitoring ............................................................................ 150 
 Quality Assurance & Quality Control ....................................................................... 151 
12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES ...................................... 152 
 Source Data/Documents ......................................................................................... 152 
 Participant & Data Confidentiality ............................................................................ 152 
 Data Collection & Storage: Privacy, Confidentiality & Security ................................ 153 
12.3.1 
LabKey Data Management ............................................................................ 153 
12.3.2 
Oregon Clinical and TransLational research institute (OCTRI) Research 
data Warehouse (RDW) ................................................................................ 154 
12.3.3 
Open Microscopy Environment (OMERO) ..................................................... 155 
12.3.4 
Biospecimens ................................................................................................ 155 
12.3.5 
Future Use of Stored Biospecimens .............................................................. 155 
12.3.5.1 
The Breast Cancer Observational Study (BCOS, IRB# 22179) .......... 155 
12.3.5.2 
BioLibrary, A Tissue Repository (IRB# 4918) ..................................... 156 
12.3.5.3 
Oregon Clinical and Translational Research Institute (OCTRI) 
Research Data Warehouse (RDW) (IRB# 4076) ................................ 156 
12.3.5.4 
Publically-Accessible Scientific Databases ......................................... 156 
 Maintenance of Records ......................................................................................... 156 
 Multicenter Guidelines ............................................................................................ 157 

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 Publication and Data Sharing Policy ....................................................................... 157 
12.6.1 
Biospecimen and Data Sharing Policy ........................................................... 158 
12.7 Conflict of Interest Policy ........................................................................................ 158 
13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS .................................................... 160 
 Ethical Standard ..................................................................................................... 160 
 Institutional Review Board....................................................................................... 160 
 Informed Consent ................................................................................................... 160 
13.3.1 
Consent Procedures and Documentation ...................................................... 160 
 Protocol Review ...................................................................................................... 161 
 Changes to Protocol ............................................................................................... 161 
14. REFERENCES ................................................................................................................ 162 
15. APPENDICES ................................................................................................................. 173 
APPENDIX A: TREATMENT ARM SELECTION CRITERIA .................................................. 174 
APPENDIX B: SMMART EXPLORATORY RESEARCH ANALYTICS PLATFORM .............. 176 
APPENDIX C: PERFORMANCE STATUS ............................................................................. 178 
APPENDIX D: CONTRACEPTION ......................................................................................... 179 
APPENDIX E: NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION
 
181 
APPENDIX F: CANADIAN CARDIOVASCULAR SOCIETY GRADING OF ANGINA 
PECTORIS ............................................................................................................................. 182 
APPENDIX G .................................................................... ERROR! BOOKMARK NOT DEFINED. 
APPENDIX G: IDENTIFICATION ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW CASES ............................................... 183 
APPENDIX H: SUMMARY LIST OF CYP1A2, CYP2C8, CYP2C19, CYP3A4, PGP, OATP1B1 
AND BCRP SUBSTRATES, INHBITORS AND INDUCERS ................................................... 187 
APPENDIX I: QT PROLONGING MEDICATIONS .................................................................. 191 
 
 

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LIST OF TABLES 
 
Table 1. Single Agent PARP inhibitors in germline BRCA 1/2 associated cancers. ...................26 
Table 2. Summary of ATR inhibitors under clinical investigation. ..............................................34 
Table 3. Regimen Description ...................................................................................................73 
Table 4. Dose reductions for olaparib treatment ........................................................................75 
Table 5. Dose reduction for olaparib treatment if participant develops moderate renal 
impairment ................................................................................................................................75 
Table 6. Dose reductions for study treatment if participant has to start taking a strong or 
moderate CYP3A inhibitor .........................................................................................................75 
Table 7. Management of anemia ...............................................................................................76 
Table 8. Management of neutropenia, leukopenia and thrombocytopenia .................................77 
Table 9. Recommended Non–Immune-Mediated Reactions treatment modifications* ...............80 
Table 10. Dose reductions for capivasertib treatment................................................................81 
Table 11. Dose modifications for general capivasertib-related toxicities ....................................81 
Table 12. Dose modifications for capivasertib-related hyperglycemia .......................................82 
Table 13. Dose modifications for capivasertib-related maculo-papular rash ..............................84 
Table 14. Dose modifications for capivasertib-related diarrhea .................................................85 
Table 15. Selumetinib recommended dosage based on body surface area ...............................86 
Table 16. Selumetinib recommended dose reduction for adverse reactions ..............................87 
Table 17. Selumetinib Recommended Management for Diarrhea .............................................88 
Table 18. Selumetinib Management of Retinal Pigment Epithelial Detachment (RPED), Central 
Serous Retinopathy (CSR), or Retinal Vein Occlusion (RVO) ...................................................88 
Table 19. Selumetinib Management of Rash .............................................................................89 
Table 20. Selumetinib Management of Paronychia ...................................................................90 
Table 21. Selumetinib Management of Elevated Creatine Kinase .............................................91 
Table 22. Selumetinib Management of Dyspnea .......................................................................92 
Table 23. Selumetinib Management of LVEF ............................................................................93 
Table 24. Guidance for dose modifications and interruptions for ceralasertib ............................94 
Table 25. Dose reduction levels for ceralasertib ........................................................................96 
Table 26. Prohibited medications - Olaparib - ......................................................................... 103 
Table 27. Restricted concomitant medications - Olaparib ........................................................ 103 
Table 28. Prohibited Concomitant Medications - Durvalumab ................................................. 105 
Table 29. Drugs known to be inhibitors of CYP3A4 or UGT2B7 .............................................. 107 
Table 30. Drugs known to be strong or moderate inducers of CYP3A ..................................... 107 
Table 31. Drugs known to be sensitive or moderate sensitive CYP3A substrates whose 
exposure, pharmacological action, and toxicity may be increased by capivasertib .................. 108 
Table 32. Drugs known to be substrates for renal or hepatic transporters whose exposure, 
pharmacological action, and toxicity may be increased by capivasertib .................................. 109 
Table 33. Study Dosing Schedule ........................................................................................... 126 
Table 34. Planned study assessments .................................................................................... 126 
Table 35. Best Overall Response: Participants with target ± non-target disease ..................... 132 
Table 36. Kurnit et al., AEs reported with olaparib and selumetinib combination ..................... 140 
 

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LIST OF FIGURES 
 
Figure 1. Efficacy of Niraparib and Anti-PD-1 in a xenograft  mouse breast cancer model ........38 
Figure 2. Decision Tree for Arm Assignment .............................................................................45 
Figure 3. Study Design for Each Arm ........................................................................................46 
 

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LIST OF ABBREVIATIONS 
 
ACC 
Advanced Computing Center 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
BID 
Twice daily 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CLIA 
Clinical Laboratory Improvement Amendments 
CoC 
National Institutes of Health (NIH) Certificate of Confidentiality 
CR 
Complete response 
CRC 
Clinical Research Coordinator 
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DLT 
Dose limiting toxicity 
DSDB 
Double stranded DNA breaks 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HBeAg 
Hepatitis B “e” antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HER2 
Epidermal growth factor receptor, type 2 
HGB 
Hemoglobin 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HR 
Homologous recombination 
HRBC 
Hormone receptor positive breast cancer 
HRD 
Homologous recombination deficiency 
IB 
Investigator’s brochure 
ICB 
Immune checkpoint blockade 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational device exemption 
IND 
Investigational new drug application 

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IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health & Science University 
ORR 
Overall response rate 
PARP 
polyADP ribose polymerase 
PD 
Progressive Disease 
PET 
Positron emission tomography 
PI 
Principle Investigator 
PO 
Per os (by mouth, orally) 
PR 
Progesterone receptor 
Pr 
Partial response 
RBC 
Red blood cell (count) 
RNI 
Reportable new information 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SSDB 
Single stranded DNA breaks 
TIL 
Tumor Infiltrating Lymphocyte 
TNBC 
Triple negative breast cancer 
TSMP 
Trial Specific Monitoring Plan 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
US 
United States  
WBC 
White blood cell (count) 
 
This document is intended to be gender neutral. The terms male and female, where stated, are 
used for identifying sex as a biological variable that is integral to medicine. 
 

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1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
 
BREAST CANCER EPIDEMIOLOGY 
 
Breast cancer is the most common cancer type among women in the United States (US), with 
an estimated 252,710 new cases expected to occur in 2017 (SEER 2017) 1.  Breast cancer can 
be classified into three distinct subgroups based on the expression of the estrogen receptor 
(ER), the progesterone receptor (PR), and the human epidermal growth factor receptor-2 
(HER2).  Hormone receptor-positive breast cancer (HRBC), defined as ER and/or PR positive 
(≥1%), is the most common subtype and constitutes around 70% of breast cancers. HER2-
positive disease, characterized by HER2 gene amplification, represents around 15-20% of 
cases; and triple-negative breast cancer (TNBC) – defined as lacking ER and PR expression 
(<1%), and negative for HER2 gene amplification – represents around 15% of cases 2,3. 
 
Despite advances in detection and treatment, breast cancer remains the second leading cause 
of death for women in the United States.  Approximately 40,000 women are expected to die 
from the disease in 2017, with most deaths attributed to the development of incurable metastatic 
disease 4,5.  The clinical development of novel targeted therapies has extended survival for 
patients with metastatic breast cancer.  In the metastatic setting, HRBC and HER2-positive 
disease have significantly better outcomes than TNBC 6.  However, virtually all patients develop 
resistance to treatment and eventually succumb to this disease.  This stresses the urgent need 
for the development of novel treatment strategies to overcome resistance and improve 
outcomes in this poor prognosis population. 
 
 
TNBC 
 
TNBC accounts for 15-20% of all breast cancers and is more common in young women and 
women of African-American or Hispanic origin 7,8.  TNBC tumors tend to exhibit more aggressive 
features, have a higher tendency for metastasis, and overall worse prognosis compared to 
HRBC and HER2-amplified disease 8.  In clinical practice, TNBC is defined as a single entity 
lacking expression of ER and PR, and lack of HER2 gene amplification. However, molecular 
analyses of TNBC have proven this is a heterogeneous disease, with multiple identified 
subtypes characterized by specific gene expression profiles 9,10.  Patients with metastatic TNBC 
have a poor median survival of ~1 year following treatment with sequential single-agent 
chemotherapy 3,11,12.  Despite an improved understanding of TNBC biology, there are currently 
no targeted agents approved to salvage TNBC that is resistant to chemotherapy 13. There is a 
need for innovative trial designs for evaluating novel therapies, identify resistance mechanisms, 
and inform the next generation of rational combinations to overcome resistance and improve 
outcomes in this poor prognosis disease.  
 
1.2.1 PARP INHIBITORS IN BRCA ASSOCIATED BREAST CANCER 
 
 
One of the most commonly dysregulated pathways in TNBC involves DNA damage response 
genes 9,10, including but not limited to BRCA 1 and BRCA2 (BRCA 1/2) genes.  Approximately 
75% of breast cancers that arise in BRCA1/2 carriers are TNBC 14.  BRCA1 and BRCA2 
defective tumors are intrinsically sensitive to PARP inhibitors, both in tumour models in vivo15,16 
and in the clinic.17  This has prompted the use of DNA damaging therapies, such as platinum 
therapies 18 and poly ADP ribose polymerase (PARP) inhibitors in the treatment of TNBC. 
Olaparib (AZD2281, KU-0059436) is a potent PARP inhibitor (PARP-1, -2 and -3) that is being 
developed as an oral therapy, both as a monotherapy (including maintenance) and for 

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combination with chemotherapy and other anti-cancer agents.  Olaparib has been shown to 
inhibit selected tumour cell lines in vitro and in xenograft and primary explant models as well as 
in genetic BRCA knock-out models, either as a stand-alone treatment or in combination with 
established chemotherapies, and has been approved as monotherapy in advanced BRCA1/2 
mutant breast cancer.  PARP inhibition is a novel approach to targeting tumors with deficiencies 
in DNA repair mechanisms.  PARP enzymes are essential for repairing DNA single-strand 
breaks (SSBs).  The mechanism of action for olaparib results from the trapping of inactive 
PARP onto the single-strand breaks preventing their repair.19,20  Inhibiting PARPs leads to the 
persistence of SSBs, which are then converted to the more serious DNA double-strand breaks 
(DSBs) during the process of DNA replication.  During the process of cell division, DSBs can be 
efficiently repaired in normal cells by homologous recombination repair (HR).  Further PARPs 
play a key role in replication fork protection and their inhibition leads to replication fork collapse 
with acquisition of DNA damage.21  Tumors with HR deficiencies (HRD), such as breast and 
ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, 
which may become lethal to cells as it accumulates22.  In such tumor types, olaparib may offer a 
potentially efficacious and less toxic cancer treatment compared with currently available 
chemotherapy regimens.  
 
In early-phase clinical trials, PARP inhibitors have shown clinical activity in patients with BRCA 
associated cancers, including breast cancer (Table 1).  These findings led to the further 
development of PARP inhibitors for the treatment of BRCA associated breast cancer. The 
OLYMPIAD trial evaluated single-agent olaparib in patients with BRCA associated metastatic 
breast cancer who have received prior chemotherapy in the metastatic setting.  In 302 evaluable 
patients, olaparib significantly improved overall response rate  (ORR) (59.9 vs. 28.8%) and 
progression free survival (7.0 vs. 4.2 months, HR 0.58 (0.43 – 0.80), p<0.001) compared to 
physician choice chemotherapy 23.  This pivotal study led to the FDA approval of olaparib for the 
treatment of metastatic BRCA1/2 associated metastatic breast cancer in January 2018, the first 
PARP inhibitor approved for breast cancer treatment.  Additionally, the EMBRACA study 
evaluated talazoparib in a similar patient population to OLYMPIAD.  In 431 evaluable patients, 
talazoparib significantly improved ORR (62.6 vs 26.2%, OR 4.99 (2.9 – 8.8), p<0.001) and 
progression free survival (8.6 vs 5.6 months, HR 0.54 (0.41 – 0.71), p<0.001) compared to 
physician choice chemotherapy 24.  
 
Table 1. Single Agent PARP inhibitors in germline BRCA 1/2 associated cancers.  
Drug 
Patients 
BCa (n) 
Efficacy 
Entire Study 
BCa 
Olaparib Phase 117 
60 patients 
BRCA1 28% 
BRCA2 8% 
9 
CBR 63% 
(BRCA mutated) 
ORR 11% 
Olaparib 400 mg BID25 
27 patients 
BRCA1 67% 
BRCA2 33% 
27 
ORR 41% 
 
- 
Olaparib 400 mg BID26 
298 patients 
BRCA1 60% 
BRCA2 40% 
62 
ORR 26.2% 
ORR 13% 

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Table 1. Single Agent PARP inhibitors in germline BRCA 1/2 associated cancers.  
Drug 
Patients 
BCa (n) 
Efficacy 
Entire Study 
BCa 
Talazoparib Phase 127 
71 patients 
BRCA1 26% 
BRCA2 25% 
14 
N/A 
ORR 50% 
CBR 86% 
Talazoparib Phase 2  
84 patients 
BRCA 100% 
49 
(prior 
platinum) 
ORR 21% 
- 
 
35 
(no prior 
platinum) 
ORR 37% 
- 
Niraparib Phase 128 
100 patients 
BRCA 29% 
4 
ORR 40% 
(BRCA mutated) 
ORR 50% 
CBR = clinical benefit rate; ORR = overall response rate 
 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB). 
 
 
IMMUNOTHERAPIES 
 
It is increasingly understood that the immune system recognizes cancers, and, under some 
circumstances, the immune system may control or even eliminate tumors29.  
 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation. The PD-1 receptor (CD279) is expressed on the surface of activated T-cells30.  It has 
2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273)31.  The PD-1 and 
PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory 
factors, which can halt or limit the development of T-cell response.  When PD-L1 binds to PD-1, 
an inhibitory signal is transmitted into the T-cell, which reduces cytokine production and 
suppresses T-cell proliferation.  Tumor cells exploit this immune checkpoint pathway as a 
mechanism to evade detection and inhibit the immune response. 
 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages 32.  Importantly, 
PD-L1 is commonly overexpressed on tumor cells or non-transformed cells in the tumor 
microenvironment 33.  PD-L1 expressed on the tumor cells binds to PD-1 receptors on the 
activated T-cells leading to the inhibition of cytotoxic T-cells.  These deactivated T-cells remain 
inhibited in the tumor microenvironment.  The PD-1/PD-L1 pathway represents an adaptive 
immune resistance mechanism that is exerted by tumor cells in response to endogenous anti-
tumor activity. 
 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination. The binding of an anti–PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells. This activity overcomes PD-L1–mediated inhibition of anti-tumor immunity. While 
functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different 
from direct agonism of a stimulatory receptor such as CD28. 

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PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti–PD-L1 
antibody could be used therapeutically to enhance anti-tumor immune responses in patients 
with cancer. Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti–PD-L1 antibody could be used to 
therapeutically enhance the anti-tumor immune response in cancer patients 34-39  with responses 
that tend to be more pronounced in patients with tumors that express PD-L1 40-42. In addition, 
high mutational burden (e.g., in bladder carcinoma 43) may contribute to the responses seen 
with immune therapy. 
 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed 
by regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a negative 
regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on antigen-
presenting cells 44.  Blockade of CTLA-4 binding to CD80/86 by anti–CTLA-4 antibodies results 
in markedly enhanced T-cell activation and anti-tumor activity in animal models, including the 
killing of established murine solid tumors and induction of protective anti-tumor immunity. 
Therefore, it is expected that treatment with an anti–CTLA-4 antibody will lead to increased 
activation of the human immune system, increasing anti-tumor activity in patients with solid 
tumors. 
 
Preclinical data have now been added to with a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and 
programmed death-ligand 1 (PD-L1) has promising clinical activity. Ipilimumab was granted 
United States (US) Food and Drug Administration (FDA) approval for the treatment of metastatic 
melanoma and is currently under investigation for several other malignancies, while nivolumab 
and pembrolizumab, two anti–PD-1 agents, and atezolizumab, an anti–PD-L1, agent have been 
granted approvals by agencies such as the US FDA and the European Medicines Agency 
approval for the treatment of a number of malignancies including metastatic melanoma, 
squamous and non-squamous cell non-small-cell lung cancer and urothelial carcinoma. In 
addition, there are data from agents in the anti–PD-1/PD-L1class showing clinical activity in a 
wide range of tumor types. 
 
1.3.1 IMMUNE CHECKPOINT BLOCKADE IN TNBC 
 
The recent advent of immune checkpoint blockade (ICB) has greatly advanced cancer therapy 
by improving efficacy and survival for a number of tumor types, especially those with high 
mutational burden and neo-antigens able to elicit anti-tumor immunity 33,36,45-52.  In patients with 
TNBC, which carries a higher mutational burden as compared to HRBC and HER2-amplified BC 
53, treatment with single-agent ICB, Pembrolizumab (PD1 inhibitor), achieved a near 20% ORR, 
with some responses being durable 54.  Additionally, recent data suggest that ICB checkpoint 
blockade may achieve higher efficacy if used in earlier lines of therapy. In metastatic TNBC, 
ORR to frontline pembrolizumab are reported at 23%, compared to approximately 5% if patients 
who had received prior chemotherapy55,56. 
 
Similarly, treatment with Atezolizumab (PD-L1 inhibitor) achieved an ORR of 13% overall in 
patients with metastatic TNBC. In that study, the ORR was 26% with Atezolizumab frontline 
therapy, compared to 11% if used as second therapy or beyond 57. Finally, the combination of 
Atezolizumab (PD-L1 inhibitor) with nab-Paclitaxel in metastatic TNBC was well tolerated, and 
resulted in a confirmed ORR of 42% in 32 evaluable patients, with highest response rates seen 

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in frontline therapy 58.  This combination is being evaluated in phase III as frontline therapy for 
metastatic TNBC (NCT02425891).  Interestingly, patients whose tumors lacked PD-L1 
expression also derived benefit from ICB 40,59-61.  These findings support the need for the 
continued development of robust biomarkers of sensitivity to ICB.   
 
Efforts to understand breast tumor complexity have revealed an important relationship between 
the tumor and the immune system.  In TNBC, tumor infiltration with cytotoxic T-lymphocytes 
(CTLs) ensuing chemotherapy-induced immunogenic cell death 62-64 is prognostic for improved 
survival 65,66 and predictive for response to NACT 67.  Unfortunately, only 11% of TNBCs have 
clinically significant CTL infiltrate (>50% infiltration) at presentation 67.  Moreover, not all tumor-
infiltrating lymphocytes (TILs) are equal, and not all patients with high TIL infiltration have a 
good prognosis.  Notably, the presence of CD8+ TILs in residual disease after NACT is a 
positive prognostic marker for survival in TNBC, whereas tumors populated predominantly with 
regulatory CD4+ TILs have poorer outcome 68,69.  These findings support the continued 
development of novel strategies to induce/augment CTL responses in TNBC.  Indeed, we have 
demonstrated in our previous pilot study (NCT03544125) that PARP inhibitors can increase 
immune invasion in breast cancer and can convert an immune desert to an immune inflamed 
environment with marked duration of patient responses to the combination of olaparib and 
durvalumab (unpublished). 
 
1.3.2 DURVALUMAB BACKGROUND/NON-CLINICAL AND CLINICAL EXPERIENCE 
 
The non-clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure.  Durvalumab is a human monoclonal antibody (mAb) of the 
immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1 and is being developed 
by AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a wholly owned 
subsidiary of AstraZeneca; and are now fully merged designated AstraZeneca). The proposed 
mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 with PD-1 
and CD80 (B7.1).  Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition 
of immune responses, including those that may result in tumor elimination.  In vitro studies 
demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T-
cells resulting in the restored proliferation of IFN-γ 70.  In vivo studies have shown that 
durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent mechanism 70.  
Based on these data, durvalumab is expected to stimulate the patient’s anti-tumor immune 
response by binding to PD-L1 and shifting the balance toward an anti-tumor response. 
Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity and 
complement-dependent cytotoxicity. To date, durvalumab has been given to more than 6000 
patients as part of ongoing studies either as monotherapy or in combination with other anti-
cancer agents.  Details on the safety profile of durvalumab monotherapy are summarized in 
Section 1.9.1.1 and Section 9.4.2. Refer to the current durvalumab Investigator’s Brochure for a 
complete summary of non-clinical and clinical information including safety, efficacy, and 
pharmacokinetics.  
 
1.3.3 RATIONALE FOR DURVALUMAB FIXED DOSING  
 
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on the PK of 
durvalumab (coefficient of ≤0.5).  The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady-state PK 

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concentrations (5th, median and 95th percentiles) using the population PK model.  A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total 
of 1000 patients were simulated using body WT distribution of 40–120 kg.  Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady-state 
PK concentrations with slightly less overall between-patient variability with fixed dosing regimen.  
 
Similar findings have been reported by others 71-74.  Wang and colleagues73 investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, with 
fixed dosing being better for 7 of 12 antibodies. In addition, they investigated 18 therapeutic 
proteins and peptides and showed that fixed dosing performed better for 12 of 18 in terms of 
reducing the between-patient variability in pharmacokinetic/pharmacodynamics parameters 74.  
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given the expectation of similar pharmacokinetic exposure and 
variability, we considered it feasible to switch to fixed dosing regimens. Based on average body 
WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is 
included in the current study. 
 
1.4 
PHOSPHOINOSITIDE 3 (PI3)-KINASE AND AKT SIGNALING IN TNBC 
 
Alterations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of 
rapamycin (mTOR) pathway are common genomic abnormalities across breast cancer 
subtypes.75  This includes both mutational events and pathway activation independent of 
mutations.  The PI3K/AKT/mTOR pathway is essential in promoting tumor cell growth and 
survival.  In general, the pathway is activated when receptor tyrosine kinases elicit activation of 
PI3K, followed by phosphorylation and activation of AKT and eventual downstream targets such 
as mTOR.75  In TNBC, several mechanisms for constitutive activation of the PI3K/AKT/mTOR 
pathway include overexpression of upstream regulators (e.g., receptor tyrosine kinase [RTKs] 
such as epidermal growth factor receptor [EGFR]), activating mutations to PI3K catalytic subunit 
α (PIK3CA), as well as loss of function or expression of phosphatase and tensin homolog 
(PTEN) and the proline-rich inositol polyphosphatase PLHP2.75-77  Though rare, activating 
mutations to AKT and mTOR have also been reported.78  Additionally, p53 inactivation has also 
been proposed to enhance the PI3K pathway.75,79  Subsequent efforts to advance the clinical 
development of PI3K pathway inhibitors have been bolstered by the clinical success of the 
mTOR inhibitor, everolimus, which is FDA-approved for hormone receptor-positive, HER2-
negative breast cancer.80  These include the clinical development of other PI3K pathway 
inhibitors such as those targeting PI3K and AKT with PI3K inhibitors being recently approved by 
the FDA.78,80-86   
 
1.4.1 COMBINED INHIBITION OF PI3K SIGNALING AND PARP 
 
Among its many roles, the PI3K/AKT/mTOR pathway is important in stabilizing and preserving 
DNA double-strand break repairs by interacting with the homologous recombination complex 
and is necessary for DNA repair during ionizing radiation.87  Interestingly, the inhibition of PI3K 
has been proposed to decrease BRCA1/2 expression and lead to homologous recombination 
deficiencies.  Moreover, in BRCA-proficient and BRCA-1 mutated TNBC models, the dual 
inhibition of PI3K with BKM120 coupled with olaparib-mediated PARP inhibition, is effective in 
reducing tumor cell growth proliferation and had synergistic in vivo anti-tumor effects.88,89  These 
and other findings have provided the basis for formal clinical trials to evaluate the combined 
PARP and PI3K pathway inhibition by our and other groups.90-93    

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Matulonis et al.90 reported on the safety and efficacy of combining a non-selective PI3K inhibitor, 
BKM120, and olaparib in patients with breast and ovarian cancers.  Though no complete 
response was observed, the authors reported response rates (i.e., PR only) of 29% and 28% 
among the ovarian and breast cancer patients, respectively, that had measurable disease. 
 
Using an accelerated intrapatient dose-escalation schema, Michalarea et al92 evaluated the 
safety of combining olaparib with the AKT inhibitor, capivasertib (AZD5363) in 20 patients with 
advanced cancers.  The established RP2D reported was capivasertib (AZD5363) at a dose of 
640 mg (PO) twice daily for 2 of 7 days, and olaparib (300 mg PO) given twice daily as part of a 
21-day cycle.  Common (>15%) grade 1-2 toxicities observed were nausea, vomiting, fatigue, 
diarrhea, and anemia.  The authors descriptively reported that PR was achieved and maintained 
for 6 months in a platinum-resistant ovarian cancer patient that characterized as being BRCA 
wild-type with PTEN LOH.  A similar PR achieved in another platinum-resistant ovarian cancer 
patient with a BRCA1 mutant lasted for greater than 5.5 months (at the time of reporting).  An 
additional but unconfirmed, PR was also seen in a patient with BRCA1-mutant breast cancer 
that was maintained for (2.5 months at the time of reporting).   
 
An ongoing phase I/II trial (NCT02208375) has sought to evaluate the safety and efficacy of 
olaparib in combination with the mTORC1/2 inhibitor, vistusertib (AZD2014), or the AKT 
inhibitor, capivasertib (AZD5363), for the treatment of patients with recurrent TNBC, 
endometrial, ovarian, primary peritoneal, or fallopian tube cancer.91,93  In the phase I portion of 
the trial evaluating the olaparib in combination with vistusertib (AZD2014), researchers reported 
a response rate of 19% and clinical benefit rate (CBR) of 34% (among 64 patients evaluable for 
response).  Across diseases, a response rate of 27%, 20%, and 6% were reported for 
endometrial, ovarian, and breast cancer, respectively.91  For the combination of olaparib and 
capivasertib (AZD5363), an overall response rate of 24% was achieved (among 30 patients 
evaluable for response); including, 7 confirmed partial responses (1 ovarian, 4 endometrial and 
2 TNBC). The response rate among patients with endometrial cancer was 50% (4/8). Moreover, 
6 additional patients had stable disease for greater than 4 months.  The RP2D established 
confirmed that olaparib (300 mg PO BID) and capivasertib (320 mg PO, BID) administered on a 
4 day on/3 day off schedule was tolerable.  Notably, the majority of patients (86%), combined 
from both phase I portions of the trial, were BRCA wild-type, further suggesting that PARP 
inhibition appears effective even in the absence of BRCA-associated and/or HR-deficiencies.93  
Altogether, these clinical findings provide preliminary evidence of synergism between olaparib 
and inhibition of PI3K/AKT/mTOR signaling, and warrants further investigation. 
 
1.4.1.1 
AKT inhibitor - Capivasertib (AZD5363) 
 
Capivasertib (AZD5363) is a pan-AKT inhibitor currently under clinical development.  Refer to 
the investigator's brochure for additional details.  
 
In the PAKT trial, the safety and efficacy of capivasertib plus paclitaxel was assessed as first-
line therapy in women with previously untreated, metastatic TNBC.86  In this study, 140 women 
(median age, 54 years) were randomly assigned to receive 90 mg/m² paclitaxel on days 1, 8 
and 15, along with 400 mg twice-daily capivasertib (n = 70) or placebo (n = 70) every 28 days.  
Participants were treated until disease progression or unacceptable toxicity.  Median follow-up 
was 18.2 months (95% CI, 13.5-24).  The authors reported a median PFS of 5.9 months in the 
capivasertib group vs. 4.2 months in the placebo group (HR = 0.74; 95% CI, 0.5-1.08).  In the 
capivasertib group, the median OS was 19.1 months, whereas the median OS was 12.6 months 

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in the placebo group (HR = 0.61; 95% CI, 0.37-0.99).  More women in the capivasertib group 
experienced grade 3 to grade 4 diarrhea (13.2% vs. 1%), infection (4.4% vs. 1%), fatigue (4.4% 
vs. 0%) and rash (4.4% vs. 0%).86 
 
The FAKTION trial was a randomized, double-blind, placebo-controlled, phase 2 trial for 
postmenopausal women with ER-positive, HER2-negative, metastatic or locally advanced 
breast cancer that had relapsed or progressed on an aromatase inhibitor.94  Participants were 
randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo 
(n=71).  The median PFS was 10.3 months (95% CI 5.0–13.2) in the capivasertib group and 4.8 
months (3.1–7.7) among those randomized to the placebo group.  An ORR in the capivasertib 
group was 41%, compared to 12% in the placebo group.  The most common grade 3–4 AEs 
observed included: hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] 
of 71 in the placebo group), diarrhea (10 [14%] vs three [4%]), rash (14 [20%] vs 0), infection (4 
[6%] vs 2 [3%]), and fatigue (1 [1%] vs 3 [4%]).  SAEs were only observed in the capivasertib 
group, including - and were acute kidney injury (2), diarrhea (3), rash (2), hyperglycemia (1), 
loss of consciousness (1), sepsis (1), and vomiting (1). The authors reported 1 death due to 
atypical pulmonary infection that was assessed as possibly related to capivasertib treatment.   
 
1.5 
RAS-RAF-MEK-ERK SIGNALING IN TNBC 
 
The Ras-Raf-MEK-ERK pathway is initiated by activation of RAS by growth factor receptors with 
subsequent activation of a Raf-Mek-Erk cascade. The cascade includes 2 isoforms of mitogen-
activated protein/extracellular signal-regulated kinase (MEK1/2), and 2 isoforms of extracellular 
signal-regulated kinase (ERK1/2).  Activation of MEK1/2 catalyzes the phosphorylation of 
ERK1/2, which in turn phosphorylates numerous cytoplasmic (e.g., p90Rsk and IKK) and 
nuclear (e.g., Ets-1, Elk‐1, c‐Fos, c-Jun and c-Myc) targets.95  Dysregulation of the Raf-MEK-
ERK pathway is commonly observed in numerous epithelial cancers and is important in driving 
cell cycle progression, proliferation, invasion, and survival.95  Though < 2% of primary breast 
cancer have mutations in the pathway constituents such as Ras and Raf, overexpression of 
receptor tyrosine kinases (e.g., EGFR) and copy number alterations in pathway constituents 
(e.g.,  amplifications or gains of KRAS and BRAF) can drive aberrant stimulation of the Raf-
MEK-ERK pathway.96-98  Moreover, crosstalk with the pro-survival PI3K/AKT, as well as loss of 
PTEN or regulatory microRNAs (e.g., Let-7) are also shown to promote altered Ras-Raf-MEK-
ERK signalling.99-101  Indeed approximately 30% TNBC have evidence of RAS pathway 
activation. 
 
Preclinical evidence using TNBC cell lines suggests that targeted inhibition of Ras-Raf-MEK-
ERK signaling reduces the proliferation and migration, and causes apoptosis and G1 arrest.102-
104  However, the potential for acquired resistance with individually targeting the Raf-MEK-ERK 
pathway suggests that inhibiting its signaling likely needs to be combined with targeted agents 
that block other pathways in order to reverse drug resistance.105-108  As such, the clinical utility of 
targeting Raf-MEK-ERK signaling as part of a therapeutic combination in patients with breast 
cancer is currently underway (NCT01467310, NCT01138085, NCT01964924, NCT02685657, 
NCT025583542).109-111   
 
Brufsky et al111 reported on preliminary findings from Cohort I of the COLET trial 
(NCT02322814), in which patients with TNBC were randomized to receive paclitaxel alone or 
the combination of paclitaxel and the MEK inhibitor, cobimetinib.  The combination of paclitaxel 
and cobimetinib achieved an ORR of 18%, whereas those that received paclitaxel alone 
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addition of cobimetinib (5.5 months vs. 3.8 months).  In cohorts II and III of the COLET trial, the 
effects cobimetinib and atezolizumab were examined either paclitaxel or nab-paclitaxel, 
respectively.  The majority of participants (~65%) in either cohort II or III had received prior 
treatment with a taxane.  The researchers observed that the combination of cobimetinib, 
atezolizumab, and paclitaxel, achieved similar responses to those that received cobimetinib, 
atezolizumab, and nab-paclitaxel (34% vs. 29%).  Interestingly, for patients that were PD-L1–
positive, there was a higher response attained among these individuals in receiving paclitaxel 
compared to nab-paclitaxel (ORR 44% vs. 33%).112  
 
1.5.1 COMBINED INHIBITION OF PARP AND RAF-MEK-ERK SIGNALING   
 
Preclinical evidence shows that cell lines rendered resistant to PARPi are characterized by 
increased activation/expression of proteins within the RAS/MAPK pathway, suggesting that this 
pathway has a role in mediating PARPi resistance.113  In tumor cells derived from breast, 
ovarian, and pancreatic cancers, which harbor RAS mutations, combined treatment with a 
PARPi and MEK inhibitor (MEKi) functions synergistically to elicit cytotoxic effects both in vitro 
and in vivo.  Moreover, the effects of the PARPi and MEKi combinations were observed as 
being independent of BRCA1/2 and p53 mutation status.  This suggests that combined inhibition 
of PARP and MEK may allow for a more generalizable approach to being able to treat patients 
with tumors lacking mutations in genes comprising HR machinery.113  In line with these findings, 
the combination of a PARPi and MEKi is currently being explored in the clinic for the treatment 
of a variety of solid tumors (NCT03162627, NCT03695380, NCT03182673).114   
 
1.5.1.1 
MEK inhibitor - Selumetinib (AZD6244) 
 
Selumetinib (AZD6244) is an orally available, selective inhibitor of MEK1 and MEK2 that is 
approved for pediatric patients, 2 years of age and older, with neurofibromatosis type 1 (NF1) 
who have symptomatic, inoperable plexiform neurofibromas (PN).currently under clinical 
development.  Refer to the investigator's brochure for additional details. 
 
Efficacy of selumetinib was investigated in SPRINT (NCT01362803), a National Cancer Institute 
(NCI) sponsored, open-label, multicenter, single-arm trial in pediatric patients with NF1 and a 
measurable target PN that could not be surgically removed without risk of substantial morbidity. 
Patients in the efficacy population (n=50) were also required to have at least one significant 
morbidity related to the target PN. Morbidities present in ≥20% of patients included 
disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and 
bladder/bowel dysfunction. Patients received selumetinib 25 mg/m2 orally twice a day until 
disease progression or unacceptable toxicity.  The reported ORR was 66% (n=33; 95% CI: 
51,79), all of whom achieved a partial response, with the majority (82%) of these responders 
sustaining their responses for ≥ 12 months. 115 
 
The anti-tumor activity of selumetinib is also currently being investigated in a variety of adult 
cancer types as a monotherapy or in combination with chemotherapies or other targeted 
agents.116-130  While early phase trials of selumetinib monotherapy in adults with advanced solid 
tumors was suggestive of target inhibition and tumor response, only modest clinical activity was 
observed in a phase 2 of patients with NSCLC.116,117,131  Several studies assessing selumetinib 
in combination with chemotherapies or other targeted agents (e.g., docetaxel, decarbazine, 
erlotinib) have reported manageable safety and tolerability profiles, often establishing a MTD or 
RP2D for selumetinib of 75 mg BID when administered as part of a combination 
regimen.119,129,132,133   

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Building on a similar approach, Kurnit et al114 provided findings of a phase 1 dose-finding study 
examining the combination of olaparib and selumetinib among 14 patients with advanced solid 
tumors.  No dose-limiting toxicities were observed for any of three dose levels were evaluated, 
and olaparib (300 mg PO, BID) and selumetinib (75 mg PO, BID) was established as the RP2D.  
No grade 4 AEs were observed.  Reported grade 3 AEs occurred with equal frequency (7%): 
fatigue, elevated aspartate aminotransferase, decreased white blood cell count, elevated CPK, 
acneiform rash, and other skin effects.  The most common AE (any grade) reported was anemia 
and hypophosphatemia (79% each).  Twelve of the 14 patients were evaluable for response 
assessment.  The combination resulted in an ORR of 17%, and a CBR of 33% (defined as CR, 
PR, and SD for ≥ 4 months).  A PR was achieved in 2 patients (1 patient with KRAS mutant 
primary peritoneal cancer, and 1 with NRAS mutant ovarian cancer).  At the time of reporting, 2 
patients remained on treatment for >15 months (1 patient with KRAS mutant primary peritoneal 
cancer, and 1 patient with KRAS mutant non-small cell lung cancer).  Notably, all patients 
achieving clinical benefit had BRCA wildtype-cancers. 
 
1.6 
ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN (ATR) SIGNALING IN 
TNBC 
 
Response to single-strand (ss) DNA damage is mediated by ataxia telangiectasia and Rad3-
related (ATR) checkpoint kinase 1 (CHK1) signaling.134  When ssDNA occurs at sites of DNA 
damage or stressed replication forks, replication protein A-coated ssDNA recruits ATR and its 
binding partner, ATR interacting protein (ATRIP).  This event triggers ATR to phosphorylate 
CHK1, which in turn promotes the proteasomal degradation of CDC25A that leads to decreased 
CDK2 activity, thereby suppressing G2-M transition and slowing S phase.134  ATR is an 
essential mediator of cellular response to DNA replication stress that is often elevated in many 
cancers, including TNBC.135  Notably, loss of G1 cell cycle checkpoint control arising from nearly 
ubiquitous presence of TP53 mutations is a recurring defect that causes even greater reliance 
on ATR-mediated intra-S and G2/M checkpoints following DNA damage.136  Preclinical studies 
have shown that in cells lacking ATM, p53, or PTEN, the inhibition of ATR can promote 
synthetic lethality, and appears to enhance the cytotoxic effects of chemotherapies (e.g., 
gemcitabine, cisplatin, doxorubicin) and radiotherapy.134,137-144  Given its importance in 
sustaining cancer cell viability, several ongoing clinical trials have sought to evaluate ATR 
inhibitors either alone or as part of a combination therapeutic regimen (Table 2).   
 
Table 2. Summary of ATR inhibitors under clinical investigation. 
ATRi 
Target cancer type 
[Trial Identifier] 
Treatment 
Biomarker selection 
M6620 
(VX-970) 
Advanced solid tumor 
[NCT03309150] 
Alone or with 
carboplatin/paclitaxel 
 
Advanced solid tumor 
[NCT02157792] 
Gemcitabine, cisplatin, etoposide, 
or carboplatin 
TP53 mutation of ATM loss 
Advanced solid tumor 
[NCT02595931] 
Irinotecan 
 
Small-cell cancers 
[NCT02487095] 
Topotecan 
DDR pathway mutations 
Urothelial carcinoma 
[NCT02567409] 
Cisplatin or gemcitabine 
p53, p21, 
and ERCC2 mutations 

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Table 2. Summary of ATR inhibitors under clinical investigation. 
ATRi 
Target cancer type 
[Trial Identifier] 
Treatment 
Biomarker selection 
Ovarian cancer 
[NCT02627443] 
Carboplatin + gemcitabine 
DNA damage assay, HRR 
mutations 
Ovarian cancer 
[NCT02595892] 
Gemcitabine 
 
mCRPC 
[NCT03517969] 
Carboplatin ± docetaxel 
 
Advanced solid tumor 
[NCT02723864] 
Cisplatin + veliparib 
DNA damage and apoptotic 
assay 
HNSCC 
[NCT02567422] 
Cisplatin + XRT 
DNA damage assay 
Brain metastases 
[NCT02589522] 
Whole brain XRT 
ATR, CHK1, RAD51, cyclin 
E, DNA-PK assay 
M4344 
Advanced solid tumor 
[NCT02278250] 
Carboplatin, gemcitabine, or 
cisplatin 
 
Ceralasertib 
(AZD6738) 
CLL, PLL or B-cell 
lymphoma 
[NCT01955668] 
Alone 
ATR targeted inhibition 
biomarker 
HNSCC 
[NCT03022409] 
Alone 
TH1/IFNγ gene and TIL state 
Refractory CLL 
[NCT03328273] 
Acalabrutinib 
 
Advanced solid tumor 
[NCT02630199] 
Paclitaxel 
 
Advanced solid tumor 
[NCT02264678] 
Carboplatin, olaparib, or 
durvalumab 
ATM deficiency 
TNBC 
[NCT03330847] 
Olaparib 
HRR mutations 
Advanced tumor 
[NCT02576444] 
Olaparib 
 
SCLC 
[NCT03428607] 
Olaparib 
 
Ovarian cancer 
[NCT03462342] 
Olaparib 
 
NSCLC 
[NCT03334617] 
Durvalumab 
 
Advanced solid tumor 
[NCT02223923] 
XRT 
 
BAY1895344 
Solid tumor and 
lymphoma 
[NCT03188965] 
Alone 
 
Adapted from Mei et al.137  
 

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1.6.1.1 
 ATR inhibitor - Ceralasertib (AZD6738) 
 
Ceralasertib (AZD6738), a potent, selective inhibitor of ATR that is under clinical investigation in 
several early-stage (phase 1 and 2) clinical trials for the treatment of solid and hematological 
malignancies.  Please refer to the ceralasertib investigator brochure for additional details. 
 
Ceralasertib monotherapy was explored in the PATRIOT collaborator study, where it was 
escalated on a continuous schedule in patients with advanced solid tumors.145  The MTD was 
160 mg BID.  In an expansion of PATRIOT, which included provision to investgate different 
schedules, an intermittent schedule of 160 mg BD ceralasertib days 1-14 every 28 days was 
much better tolerated than continuous dosing. The PATRIOT study declared 160 mg BID 
ceralasertib on an intermittent schedule a futue RP2D (1915 - A Phase I study of ATR inhibitor, 
AZD6738, as monotherapy in advanced solid tumours (PATRIOT Part A, B).146  The PATRIOT 
study did not permit escalation of the 160 mg BID dose on an intermittent schedule.  However, 
240 mg BD days 1-14 has been tested in combination with durvalumab in a company sponsored 
trial and with paclitaxel in a collaborator trial, and found to be tolerated.  The confirmed RP2D 
for ceralasertib monotherapy is 240 mg BID for days 1-14 of every 28 day cycle.  
 
Results from preclinical studies suggest that the cytotoxicity mediated by PARP inhibitors can 
be further potentiated by targeting the G2/M cell cycle checkpoint to force mitotic entry in the 
presence of DNA lesions.142,147,148  The clinical efficacy of combined ATR and PARP inhibition 
has, unfortunately, not been fully realized.  The phase 2 VIOLETTE study of patients with TNBC 
is assessing the efficacy of olaparib in combination with ceralasertib or the wee1 inhibitor, 
adavosertib (NCT03330847).149  This combination of olaparib and ceralasertib, however, did not 
meet its predefined criteria for efficacy in the BRCA-mutant stratum and the study was closed 
early. These findings have instead prompted interest in evaluating ceralasertib as a 
monotherapy, but at a higher dose than that used in VIOLETTE.  The study described herein 
will investigate the effects of single agent ceralasertib.  
 
The dose of ceralasertib as monotherapy to be studied is 240 mg twice daily from Day 1 to Day 
14 of every 28-day cycle. This dose has been used as monotherapy and in combination with 
durvalumab 1500 mg administered on Day 1 of each 28-day cycle in Study D5330C00004 
(NCT02264678) where 29 patients with NSCLC and SCHNN have been treated.  Ceralasertib 
240 mg twice daily was given as monotherapy in Cycle 0 for 14 days (Days 1 to 14) and then 
from Day 15 to Day 28 in each subsequent cycle in combination with durvalumab.  
 
Ceralasertib 240 mg twice daily from Day 15 to Day 28 of every 28-day cycle in combination 
with durvalumab 1500 mg administered on Day 1 of each 28-day cycle is also used in an 
ongoing collaborator (ESR) study in South Korea in patients with malignant melanoma (27 
patients) and metastatic gastric cancer (31 patients) (as of 30 April 2020) (NCT02630199).  This 
dose schedule of AZD6738 was not formally tested in PATRIOT (NCT02223923) in which 160 
mg twice daily from Day 1 to Day 14 of every 28-day cycle, administered to 20 patients in the 
expansion cohort, was well-tolerated.  
 
Preliminary safety data has shown that ceralasertib 240 mg twice daily from Day 1 to Day 14 of 
every 28 day cycle is well tolerated as monotherapy as well as in combination with durvalumab 
(Study D5330C00004). 
 
The dose level of 240 mg twice daily is predicted to maintain ceralasertib concentrations above 
the estimated concentration of an inhibitor where ATR catalytic activity is reduced by 90% 

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(IC90) threshold for 12 hours in 90% of patients.  A sigmoid model links ceralasertib 
monotherapy exposure with the difference between monocytes (PD modulation) and platelet 
decrease (the main related haematological toxicity of ceralasertib). 
 
Based on the aforementioned data, the use of ceralasertib 240 mg twice daily as monotherapy 
from Day 1 to Day 14 of every 28-day cycle in this module is justified.  Notably, ceralasertib 240 
mg twice daily as monotherapy from Day 1 to Day 14 will also be administrated in the study 
PLANETTE (study title “A Modular Phase 2a, Open Label, Multicentre Study to Investigate 
DNA-Damage Response Agents [or Combinations] in Patients with Advanced Cancer whose 
Tumours contain Molecular Alterations”) in which at least 25 patients with advanced solid 
tumours and 27 patients with mCRPC will initially be enrolled.   
 
 
RATIONALE  
 
Preclinical and clinical data have validated the efficacy of PARP inhibitors through synthetic 
lethality in tumors homologous recombination deficiency (HRD).  However, it rapidly became 
clear that PARP inhibitors trapped PARP on DNA, creating double-strand breaks (DSB) that are 
difficult to repair 150.  Furthermore, PARP is a component of the replication fork, and inhibition of 
PARP results in replication fork collapse and induction of DNA damage.21  The PARP trapping 
activity clearly contributes to both efficacy and toxicity, as the phase II doses for trapping PARP 
inhibitors correlate with their trapping activity and not with their ability to inhibit PARP enzyme 
activity.  Thus, two approaches could increase the utility of PARP inhibitors: first, to induce HRD 
in HR competent cells and secondly, to capitalize on DNA damage induced by PARP and the 
toxic DSB induced by PARP trapping.  Clinical trials have shown high response rates for PARP 
inhibitors in BRCA associated TNBC, with a more limited set of responses in BRCA wild-type 
TNBC showing a DNA damage repair signature.27,151  Unfortunately, responses are not durable, 
stressing the need to understand resistance mechanisms to PARP inhibitors and develop 
combination therapies to improve responses. 
 
Multiple mechanisms of resistance to PARP inhibitors have been identified, with most 
mechanisms based on preclinical models. Resistance falls into two broad categories; 
endogenous resistance due to increased HR repair capacity such as that mediated by RAS 
mutations 113 and acquired mechanisms of resistance, which fall into three categories: (a) 
reconstitution of HR competence indicated by reconstitution of Rad51 foci 150,152-155, (b) 
replication fork protection and (c) a miscellaneous group with multiple different mechanisms 
150,156-158.  There is mounting evidence showing that PARP inhibition induces activation of 
numerous signaling pathways (i.e., PI3K-AKT, Raf-MEK-ERK), as well as immune activation.159  
Exploiting the crosstalk among these pathways, the Adaptive Multi-Drug Treatment of Evolving 
Cancers (AMTEC) study will investigate the combined inhibition of PARP with AKT, MEK, or 
PD-L1, as well as ATR inhibition alone, as a novel means to improve outcomes of patients with 
metastatic TNBC.  In this study, participant assignment to a study arm will be informed using a 
decision-tree algorithm that utilizes biomarker-driven signatures indicative of immune cell 
activation, or perturbations in PI3K-AKT or Raf-MEK-ERK signaling, which can be exploited 
using targeted agents (refer to Section 3.1 and Appendix A).      
 

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1.7.1 TARGETING PARP AND THE IMMUNE RESPONSE 
 
Additionally, preclinical studies have demonstrated 
immunomodulatory properties for PARP inhibitors 
through increased antigen presentation as well as 
recruitment of cytotoxic T-lymphocytes 160,161, both 
properties that may predict benefit of immune 
checkpoint blockade (ICB). Importantly, we have 
demonstrated 
PARP 
inhibitors 
and 
ICB 
are 
synergistic in syngeneic breast cancer models that 
are BRCA1/2 wild type and competent for DNA 
damage repair through induction of a STING 
response 
(Fig.1). 
Importantly, 
multiple 
PARP 
inhibitor and ICB trials are underway, with preliminary 
and exciting emerging clinical trial data.  
 
In the TOPACIO trial, the combination of niraparib and pembrolizumab in patients with platinum-
resistant ovarian cancer and TNBC was shown to be well-tolerated and had clinical activity in  
BRCA-mutant with a lower rate of response in BRCA-wildtype tumors 162. Additionally, the 
MEDIOLA study reported the combination of olaparib and durvalumab (MEDI4736) in metastatic 
BRCA associated breast cancer to be well-tolerated, and have excellent disease control rate on 
preliminary analysis.163  Finally, the proposed dosing combination of olaparib 300 mg orally twice 
daily and durvalumab at 1500 mg IV every 4 weeks has been reported to be safe and well-
tolerated in a phase 1 study looking at recurrent women's cancers, including TNBC164. No dose-
limiting toxicities were reported with the combination of olaparib and durvalumab, and the majority 
of adverse events were grade 1-2164.  
 
This study arm will focus on patients with BRCA-wildtype biopsy-proven metastatic TNBC.  PARP 
inhibitors and ICB have each shown single-agent activity in TNBC. The preclinical and clinical 
data (Section 1.2) validate the rationale for combining PARP inhibitors with ICB for the treatment 
of metastatic TNBC, including patients without abnormalities in BRCA1/2, with the aims of 
augmenting responses to therapy and, more importantly, achieving durable responses in this poor 
prognosis population.  
 
1.7.2 COMBINED TARGETING OF PARP AND CAPIVASERTIB  
 
The preliminary evidence showing synergy in the combined inhibition of PARP and components 
of the PI3K-AKT pathway in several solid tumors, including TNBC, is compelling.90-93  Moreover, 
the enhanced sensitivity to PARP inhibitors following inhibition of PI3K-AKT signaling occurs in 
both BRCA-proficient and -deficient TNBC cells, suggesting that a novel treatment strategy is 
possible regardless of BRCA mutational status.88,165,166  Additional clinical information is 
critically-needed to fully understand the therapeutic potential of this combination in the treatment 
of TNBC and, in particular, biomarkers able to identify the subpopulation of patients likely to 
benefit from the combination.  In the current study, patient-specific selection criteria will be used 
to guide the assignment of participants to receive the combination of olaparib and capivasertib.  
The dosing for this combination is based on a previous phase 1 trials that established olaparib 
(300 mg PO BID) and capivasertib (400 mg PO, BID) administered on a 4 day on/3 day off 
schedule as being safe and tolerable.93   
 
1.7.3 COMBINED TARGETING OF PARP AND SELUMETINIB 
 
Figure 1. Efficacy of Niraparib and Anti-PD-1 
in a xenograft  mouse breast cancer model 

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The combined inhibition of PARP and MEK provides a compelling strategy to increase 
apoptosis in a variety of solid tumors.  Particularly, the inhibition of MEK alters the apoptotic 
balance, induces deficiencies in homologous repair mechanisms, and reduces DNA damage 
checkpoint activity.113  Translating these findings to the clinic, however, has yet to be fully 
explored, and it remains unknown if patients with TNBC can benefit from this combined 
treatment approach.  In the current study, participants assigned to this treatment cohort will 
receive olaparib (300 mg PO, BID) and selumetinib (75 mg PO, BID) based on previously 
established RP2D.114    
 
1.7.4 ATR TARGETING BY CERALASERTIB 
 
The activated ATR-Chk1 pathway affects multiple DNA damage and replication checkpoint 
responses.  Inhibiting ATR alters the G2/M cell cycle checkpoint to promote early mitotic entry 
even with DNA lesions present.137,167  Given the prevalence of DNA damage repair defects in 
TNBC, targeting ATR for inhibition is a relevant strategy to increasing DNA damage and 
inducing mitotic crisis.  To further explore the anti-tumor effects of ATR inhibition in TNBC, 
participants that do not have a molecular signature indicative of immune cell activation, or 
perturbations to AKT or MEK signaling, will be assigned to receive ceralasertib.  In this 
treatment arm, participants will receive ceralasertib monotherapy (240 mg PO BID) on days 1 to 
14 of each 28 day cycle.   
 
 
EXPLORATORY STUDIES BACKGROUND 
 
Rapid improvements in biomedical technology have revolutionized our understanding of cancer 
biology and allowed us to map the genetic landscape for different tumors. While novel therapies 
targeting cancer-specific alterations have generated responses, these are typically short-lived, 
and resistance to single-agent therapy almost universally emerges.  There is a need to 
understand mechanisms of resistance to therapy and develop rational combinations able to 
augment and extend responses to treatment. Based on our institutional experience, serial 
metastatic breast cancer biopsies are safe and provide high yield samples for multi-omics 
analysis. To this end, the proposed study includes an adaptive biomarker platform that 
leverages serial tissue collection which can be correlated with clinical responses to therapies to 
inform on predictive biomarkers. This aims to:  
a) Identify mechanisms of (1) adaptive (2) immunologic and (3) tumor microenvironmental 
sources of resistance to therapy 
b) Develop strategies to induce synthetic lethality, rewire the tumor microenvironment, 
manage tumor heterogeneity and bypass adaptive resistance to therapy, and establish 
methods to optimize combinatorial therapy selection through real-time pharmacologic 
evaluation for participants 
c) Achieve durable response rates with acceptable toxicity. 
 
1.8.1 PRE-TREATMENT BIOPSY: 
 
This biopsy will provide an unperturbed initial assessment of tumor biology, following which 
participants will proceed with monotherapy for 4 weeks of treatment.  All pre-treatment biopsies 
will undergo clinically validated (i.e., CLIA) assays (Refer to Section 7.5).  
 
1.8.2 ON-TREATMENT BIOPSY: 
 
A repeat on-treatment biopsy will be performed after participants have completed a 2-week 
induction of olaparib monotherapy.  Following single-agent therapy, the multi-omics performed 
on this repeat biopsy will allow for a deeper analysis of tumor biology through: confirming 

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pharmacodynamics effects of the monotherapy agent (i.e., confirmation of drug hitting target), 
revealing how the tumor ecosystem has adapted to therapeutic stress and identifying emerging 
mechanisms of resistance and therapeutic opportunities such as immune system activation.  
 
1.8.3 POST-PROGRESSION BIOPSY: 
 
This optional biopsy will inform on mechanisms of tumor escape from combination therapies.  
Findings from multi-omics analysis of this tissue sample can be compared to the on-treatment 
biopsy results to reveal mechanisms of resistance to mono vs. combination therapy and help 
inform future treatments for enrolled participants.  
 
1.8.4 CELLULAR AND MOLECULAR PROFILING OF SERIAL BIOPSIES 
 
The exploratory research aims of this study are intended to elucidate mechanisms by which 
metastatic breast cancers develop resistance, either inherent or acquired, to targeted therapies 
and when and how PARP inhibition sensitizes to immune checkpoint blockade as well as 
emerging mechanisms to immune checkpoint blockade. Possible resistance mechanisms 
include: a) tumor intrinsic genomic instability and epigenomic plasticity; b) events extrinsic to the 
cancers cells, including chemical and mechanical signals from the microenvironments, 
production of mechanical extracellular matrix barriers and/or changes in vasculature that reduce 
drug and/or immune cell access; c) nanoscale cancer cell-microenvironment interactions that 
reduce drug efficacy; d) and a plethora of immune resistance mechanisms such as loss of HLA 
expression and antigen presentation or immune exhaustion.  These mechanisms likely vary 
between participants and within individual participants and change with time as tumors respond 
to therapeutic attack.   
 
The overarching aim of these exploratory studies will enable discovery of mechanisms of 
resistance that arise in individual participants with metastatic breast cancer undergoing 
treatment with targeted and/or immune therapies.  Identified assays and biomarkers can then be 
further developed and validated in CLIA fashion to guide therapeutic decision making.  To 
address this research objective, a series of exploratory research analytics will be conducted on 
available blood and tissue specimens (refer to Appendix B for additional information).  
 
 
POTENTIAL RISKS AND BENEFITS 
 
1.9.1 KNOWN POTENTIAL RISKS  
 
Potential toxicities of the study drug combinations are detailed in Section 9.4.  Additional on-
study risks to participants are associated with a tumor tissue biopsy, which may include 
bleeding, infection, pain, and damage to the organ in which the cancer resides.  
 
1.9.1.1 
Immune checkpoint blockade  
 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system, however, there is the potential 
for adverse effects on other tissues. 
 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which may 

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require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ 
system and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and liver enzyme 
elevations, skin events such as rash and dermatitis and endocrinopathies including hypo- and 
hyper-thyroidism.  Refer to the durvalumab investigator brochure for additional risk information. 
 
1.9.1.2 
Capivasertib 
 
The safety profile for capivasertib is still emerging.  Based on clinical data available to date, the 
risks associated with capivasertib are as follows: 
• Important Identified Risks : Diarrhea, rash, hyperglycemia, hypersensitivity 
• Identified Risks : Nausea and vomiting, stomatitis, dry skin, pruritis, decreased appetite, 
pyrexia, erythemea multiforme.  Refer to the capivasertib investigator brochure for additional 
risk information. 
 
The overlapping toxicities in this study for olaparib and capivasertib are diarrhoea, rash, nausea, 
vomiting, decreased appetite and stomatitis. 
 
Management of capivasertib related toxicities will be as follows 
• 
Diarrhea, rash- A recommended toxicity management algorithm (see Sections 6.3.4.4 
and 6.3.4.6) provided with the protocol will aid consistent and standardised management 
of capivasertib related diarrhoea and rash across the study. 
• 
Nausea, vomiting, decreased appetite and stomatitis - these can be managed with 
treatment and interruptions to capivasertib dosing using 'Dose Modifications due to 
general capivasertib-related toxicities'. These are expected to be evaluated and treated 
by investigators according to local practice. 
 
1.9.1.3 
Selumetinib 
 
Possible risks associated with selumetinib include: gastrointestinal events (e.g., diarrhea, 
nausea, vomiting), dermatological events (e.g., acneiform rash), fatigue, pyrexia, respiratory 
event (e.g., dyspnea, ILD-type events, including symptoms of shortness of breath, fatigue, 
cough and/or fever), hypertension, peripheral edema, visual function (e.g., blurred vision, central 
serous retinopathy/ retinal pigment epithelial detachment), hyperphosphatemia, as well as 
increases in creatine phosphokinase.  Refer to the selumetinib investigator brochure for 
additional risk information. 
 
1.9.1.4 
Ceralasertib 
 
The safety profile for ceralasertib is still emerging.  Common AEs, defined as those occurring in 
>10% of patients who received ceralasertib monotherapy include: nausea, fatigue, anemia, 
thrombocytopenia and vomiting.  The most common SAEs include: anemia, decreased appetite, 
febrile neutropenia, platelet count decreased, and pneumonia.  Refer to the ceralasertib 
investigator brochure for additional risk information. 
 
1.9.2 KNOWN POTENTIAL BENEFITS 
 
Given the lack of treatment options for patients with advanced cancers such as TNBC, the 
current study may provide access to a new treatment approach not previously available.  It 

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cannot, however, be guaranteed that participants in this study will directly benefit from treatment 
during participation, as the clinical trial is designed to provide information about the safety and 
effectiveness of the investigational approach. 
 
 
 
 

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2. OBJECTIVES 
 
 
PRIMARY OBJECTIVES 
 
Assess overall response to treatment  
 
 
SECONDARY OBJECTIVES 
 
1. Assess participant benefit from treatment 
2. Determine the time to disease progression following response to study therapy  
3. Determine time to first disease progression or death of participants enrolled on the study 
4. Determine survival of participants enrolled on the study  
5. Assess safety and tolerability of the proposed therapy 
 
 
EXPLORATORY OBJECTIVES 
 
1. To assess a change in quality of life (QOL) as measured by European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-
C30) in each treatment arm. 
2. To assess a change in QOL as measured by Breast Cancer-Specific Quality of Life 
Questionnaire (QLQ-BR23) in each treatment arm. 
3. Examine response rates depending on tumor characteristics  
4. Identify predictive biomarkers of sensitivity to therapy  
5. Identify emerging mechanism of resistance to therapy.  
6. Determine changes in tumor cells and the tumor microenvironment induced by PARP 
inhibitors.  
 

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3. STUDY DESIGN AND ENDPOINTS 
 
 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 10, SAFETY STATISTICAL CONSIDERATIONS for additional information 
regarding statistical methods used in this study. 
 
This is a  non-comparative, multi-arm, open-label phase II study to assess the efficacy of 
olaparib in combination with either durvalumab, selumetinib, or capivasertib, or ceralasertib 
monotherapy for the treatment of patients with metastatic TNBC.  Participants must meet all of 
the inclusion criteria, have none of the exclusion criteria, and have provided written informed 
consent before the conduct of any screening test(s) not performed routinely in their treatment. 
 
This study will enroll participants with metastatic TNBC (defined as ER <10%, PR <10%, and 
HER2 non-amplified).  Individuals with luminal androgen receptor (LAR) subtype of TNBC, 
defined as androgen receptor (AR) ≥80% expression by IHC will be excluded from participation.  
Participants with biopsy-proven TNBC will undergo a pre-treatment biopsy, following which all 
participants will start a 4-week induction treatment with olaparib (300 mg PO BID).  Participants 
will undergo a repeat on-treatment biopsy 2 weeks (± 7 days) after starting olaparib 
monotherapy (i.e., Cycle 1, Day 14 ± 7 days).  Following the 4-week olaparib induction 
treatment, participants will then be assigned to one of four treatment arms: 
Arm 1 – olaparib (300 mg BID) given from Days 1 to 28, will be administered in combination 
with durvalumab (1500 mg IV every 4 weeks), 
Arm 2 – olaparib (300 mg PO, BID) given from Days 1 to 28, will be administered in 
combination with selumetinib (BSA dosing per Table 15) for 28 days  
Arm 3 – olaparib (300 mg BID) given from Days 1 to 28, will be administered in combination 
with capivasertib (400 mg PO BID) that is given on a 4 day on/3 day off schedule for 
28 days. 
Arm 4 –ceralasertib (240 mg PO BID) that is given on Days 1 to 14 of the 28-day treatment 
cycle.  
 
Results obtained from one or more clinically-validated assays (i.e., laboratory-diagnostic test 
[LDT] or FDA-cleared or approved in vitro diagnostic [IVD] test) using either the pretreatment 
and/or on-treatment biopsy (i.e., Cycle 1, Day 14 ± 7 days) may be used to determine treatment 
assignment based on the decision tree shown in Figure 2 and the associated criteria described 
in Appendix A.  Note that the planned Cycle 2 Day 1 start of olaparib in combination with 
durvalumab, capivasertib, or selumetinib, or ceralasertib monotherapy treatment may be 
delayed up to as much as 14 days to allow for the return and analysis of clinical laboratory 
results.  
 
Following the guidelines described in Figure 2, participants with demonstrable immune 
activation following olaparib monotherapy lead-in will be assigned to Arm 1.  Individuals not 
qualifying for Arm 1 will nex be considered for Arms 2, 3, or 4.  Participants with aberrant 
activation of the RAS-MEK-ERK pathway will be assigned to Arm 2.  This is due to evidence 
that RAS-MEK-ERK pathway activity renders tumors resistant to PARP inhibition, and MEK 
inhibitors reverse the resistance.  Individuals not qualifying for Arm 2 will next be considered 
based on an altered PI3K-AKT pathway, and if present, then they may be assigned to Arm 3.  
This is based on our evidence of synergy between PARP and AKT inhibitors in preclinical and 
clinical studies.  Any remaining participants will be assigned to Arm 4, which is considered the 
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treatment arms. However, it is expected that most of these patients will have a signature 
indicative of high replication stress and therefore ceralasertib is an appropriate investigational 
treatment.  Once Arm 1 has completed enrollment, considerations to participant assignment will 
use decision-tree guidelines beginning with Arm 2, and repeat itself in an iterative process.    
 
Participants with or without BRCA mutations are eligible for assignment to treatment Arms 1, 2, 
3, or 4.  The germline mutational status of BRCA among participants at enrollment will be 
carefully assessed to avoid unwanted overrepresentation or imbalance between treatment arms 
– as such the total number of BRCA mutant participants to any of the study arms should not 
exceed more than 20% per each stage (i.e., 4 BRCA mutant participants/arm, 2 each in stage I 
and II of each arm).   
 
Regardless of treatment assignment, participants are planned to receive 12 cycles of their 
assigned combination therapy but may continue on therapy beyond the planned 12 cycles in the 
absence of disease progression or unacceptable toxicity.  Participants will also be offered an 
optional repeat biopsy on disease progression.  Up to 132 participants are planned for 
enrollment to this study. 
 
The trial will be conducted using separate two-stage analyses for each study arm (Figure 3).  
Refer to Section 10.3.1 for additional information pertaining to statistical design.  
 
In Arm 1, up to 15 participants will be enrolled and analyzed in stage I. If there are 2 or fewer 
responses among these initial participants the study arm will be stopped, otherwise an 
additional 13 participants will be enrolled and treated in stage II (n = 28) (Figure 3).  
 
Figure 2. Decision Tree for Arm Assignment 

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For Arms 2, 3, and 4, up to 11 participants will be enrolled and treated in stage I of each 
experimental arm.  If, within a study arm, there are 1 or fewer responses among the first 11 
participants, then that study arm will be terminated in stage I, otherwise, an additional 11 
participants will be accrued to stage II (n = 22 per each study arm) (Figure 3).  
 
 
At the time of interim analysis for Arms 2 and 3 only, if there are 5 or more responses among 
the first 11 participants in stage I of each study arm, then an expansion biomarker negative 
cohort may be evaluated within that study arm.  In such cases, participants enrolled into the 
study may be assigned to a biomarker negative expansion independent of any pre-defined 
molecular characteristic described in Figure 2.  Each study arm that opens a biomarker 
negative expansion cohort will enroll up to 9 participants in stage I.  If 1 or less out of the first 9 
participants respond, then the repective study arm’s expansion cohort will be terminated, 
otherwise an additional 10 participants will be accrued to stage II (n = 19 per each study arm 
that has a biomarker negative expansion cohort) (Figure 3). NOTE: The biomarker selection 
arm will continue to enrolling in stage provided interim milestones are met. The biomarker 
negative expansion cohorts will only open after completion of enrolment of their respective arms 
(Arm 2 or 3). If, per study design, a biomarker negative arm is warranted, treatment arm 
assignment will be described in a planned protocol amendment prior to initiation of the 
expansion biomarker negative arm(s).  
 
3.1.1 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The use of PARP inhibitors in TNBC has been majorly focused on BRCA-mutant tumors.  This 
Figure 3. Study Design for Each Arm 

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proposal aims to leverage robust preclinical and early clinical data to expand this benefit to 
BRCA-wildtype TNBC, which represents a poor prognosis population.  
The TNBC target population in this study will not include LAR TNBC, defined as those 
expressing the AR ≥80% by IHC.  The rationale for excluding this TNBC subtype stems from our 
experience across 3 separate clinical trials (NCT03162627, NCT03544125, NCT03801369), 
which to-date, has revealed that all patients with LAR have demonstrated rapid progression 
(unpublished).  Further, pathway analysis indicates that PARP inhibitors have modest impact on 
LAR tumors and the tumor microenvironment. LAR tumors do not exhibit immune activity that 
would be expected to increase response to PARP and PD-L1 inhibitors. Finally, AR expression 
in breast cancer cell lines induces resistance to PARP inhibitors (unpublished). 
The initial biopsy will provide a baseline unperturbed view of systems biology before the 
initiation of any therapy. The second biopsy will be performed after participants have received 
monotherapy with olaparib, and before durvalumab is added to their treatment.  This approach 
will allow us to 1) evaluate if olaparib is inhibiting the target adequately; 2) understand the 
impact of olaparib on the tumor ecosystem; 3) identify emerging mechanisms of primary, 
adaptive, and acquired resistance to olaparib; and 4) determine effects of PARP inhibitors on 
the immune system.  We will thus be able to learn deeply from each participant biopsy to 
understand how the tumor ecosystem has adapted to therapeutic stress.  This information can 
then be correlated to participant outcomes to develop biomarkers of sensitivity to therapy and 
build novel rational combinations aimed at overcoming treatment resistance.   
 
This is a non-comparative study, and the efficacy and safety of the assigned study interventions 
for each treatment arm (i.e., Arm 1, Arm 2, Arm 3, or Arm 4) will be evaluated independently of 
one another.  For each treatment arm, the primary endpoint is to assess the ORR following 
completion of on-study treatment with olaparib in combination with durvalumab, capivasertib, or 
selumetinib, or ceralasertib monotherapy, respectively.  Secondary efficacy endpoints will 
include clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), 
and overall survival (OS) of enrolled participants.  Additional secondary endpoints on this study 
include assessing the safety and tolerability of each combination therapy, in which the severity 
of on-treatment adverse events will be collected as per CTCAE 5.0.  Post-treatment follow-ups 
will occur for a period of 1-year. 
 
For those assigned to Arm 1, the study aims to achieve a primary endpoint of an ORR of 35% 
compared to 15% historical control for ICB in TNBC (refer to section 1.2.2).  The recently 
presented Topacio study evaluated a similar combination of Niraparib and Pembrolizumab in 
metastatic BRCA-mutant as well as BRCA-wildtype TNBC, with a reported ORR of 28% in that 
study. The response in BRCA-wildtype TNBC was lower and transient.  Patients on the Topacio 
trial could have received up to 2 lines of therapy in the metastatic setting, and almost 40% had 
received prior platinum therapy. Response to PARP inhibitors has been reported to be lower 
following platinum therapy, and in our practice clinical trial enrollment, taxanes and eribulin are 
usually preferred agents for metastatic TNBC prior to using platinum therapy. Additionally, 
Topacio did not restrict enrolment of LAR TNBC, who we have observed do not benefit from this 
combination in our experience. We thus expect a significantly smaller proportion of patients to 
be exposed to platinum prior to enrollment, which will increase the chances of response to our 
proposed combination, hence the improvement in 20% in ORR that is assumed. 
 
For those assigned to Arms 2-4, the study aims to achieve a primary endpoint of an ORR of 
40% compared to 15% historical control.  Prior studies show that responses to PARP inhibitor 
monotherapy, including olaparib, varies widely (Table 1).  Among patients with 
advanced/recurrent TNBC or hormone-receptor-positive breast cancer, PARP inhibitor 
monotherapy achieves responses of 12-47% among those with a BRCA mutation, whereas 
those with BRCA wild-type breast cancer achieve far lower responses (0-15%).17,25,26,28,169,170  

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Although Arms 2-4 of this trial permit participation of patients with wild-type or mutant BRCA, the 
latter constitutes only 10-20% of all TNBCs and will represent a small subset of within each 
treatment arm.  As such, establishing a historical response of 15% best captures the reported 
response rate for PARP inhibitors in this mixed population.  Though predominantly comprising 
patient populations with BRCA mutations, prior reports show that the combination of olaparib 
and paclitaxel or carboplatin can achieve responses between 33-87.5%; and 28% in 
combination with the PI3K inhibitor, bupralisib.90,171,172  Building on these studies within our trial, 
we will test the assumption that a 25% increase in response associated with olaparib in 
combination with selumetinib, or capivasertib, or ceralasertib monotherapy is clinically 
meaningful.    
 
 
STUDY ENDPOINTS 
 
3.2.1 PRIMARY ENDPOINT 
 
Objective 
Endpoint 
Start  
End  
1. Assess overall 
response to 
treatment 
1. ORR olaparib + durvalumab (Arm 1),  
ORR olaparib + selumetinib (Arm 2),  
ORR olaparib + capivasertib (Arm 3), 
ORR ceralasertib (Arm 4) 
From 
completion 
of Cycle 1 
End of 
treatment 
[EOT] 
 
3.2.2 SECONDARY ENDPOINTS 
 
Objective 
Endpoint 
Start  
End  
1. Assess 
response to 
treatment 
1. CBR olaparib + durvalumab (Arm 1), 
CBR olaparib + selumetinib (Arm 2), 
CBR olaparib + capivasertib (Arm 3), 
CBR ceralasertib (Arm 4) 
From 
completion 
of Cycle1 
End of 
Treatment 
(EOT) 
2. Determine the 
time to disease 
progression 
following 
response to 
study therapy 
2. DOR olaparib + durvalumab (Arm 1), 
DOR olaparib + selumetinib (Arm 2), 
DOR olaparib + capivasertib (Arm 3), 
DOR ceralasertib (Arm 4) 
From time 
of first CR 
or PR of 
objective 
response; 
from end of 
cycle 1 for 
stable 
disease 
End of 
Treatment 
(EOT) 
3. Determine time 
to first disease 
progression or 
death of 
participants 
enrolled on the 
study 
 
3. PFS olaparib + durvalumab (Arm 1), 
PFS olaparib + selumetinib (Arm 2), 
PFS olaparib + capivasertib (Arm 3), 
PFS ceralasertib (Arm 4) 
From 
completion 
of cycle 1 
Progression 
or death (any 
cause) up to 
1 year post-
treatment 
4. OS olaparib + durvalumab (Arm 1), 
OS olaparib + selumetinib (Arm 2), 
OS olaparib + capivasertib (Arm 3), 
OS ceralasertib (Arm 4) 
From 
completion 
of cycle 1 
Death (any 
cause) up to 
1 year post-
treatment 
4. Assess safety 
and tolerability 
of the proposed 
therapy 
5. Incidence of ≥ Grade 3 toxicities (per 
CTCAE v5.0) for each proposed 
treatment arms 
Day 1 
3 months 
post-
treatment 

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3.2.3 EXPLORATORY ENDPOINTS 
 
Objective 
Endpoint 
Start  
End  
1. To assess a 
change in QOL 
as measured by 
EORTC QLQ-
C30 in each 
treatment arm. 
1. Change From Baseline to end of 
treatment in EORTC QLQ-C30 - Total 
Score 
Day 0 
[Baseline] 
End of  
Treatment 
[EOT] 
2. To assess a 
change in QOL 
as measured by 
EORTC 
QLQBR23 
3. Change From Baseline to end of 
treatment in EORTC QLQBR23 -Total 
Score 
Day 0 
[Baseline] 
End of 
Treatment 
[EOT] 
 

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4. STUDY ENROLLMENT AND WITHDRAWAL 
 
 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ability to understand and the willingness to sign a written informed consent document. 
2. Participants are ≥ 18 years old at time of informed consent. 
3. Metastatic TNBC, as defined by: 
a. ER and PR negative as defined as ER <10% and PR <10% by immunohistochemistry 
according to American Society of Clinical Oncology (ASCO)/College of American 
Pathologists (CAP) guidelines for hormone receptor testing 
b. HER2 non-amplified per ASCO/CAP guidelines, defined as:  
i. IHC score 0/1+ 
ii. IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to CEP17 
<2.0, and if reported, average HER2 gene copy number <4 signals/cells; or 
iii. ISH non-amplified with a ratio of HER2 to CEP17 <2.0, and if reported, average 
HER2 gene copy number <4 signals/cells 
4. Participants with or without germline BRCA mutated TNBC are eligible for study participation 
5. Participants must have at least one measurable site of disease as defined by RECIST v1.1 
(refer to Section 8) that is amenable to biopsy.  
6. Prior therapies for metastatic breast cancer 
a. Frontline patients who have not received prior systemic therapy for metastatic breast 
cancer are eligible. 
b. Patients who have received ≤ 2 prior chemotherapy regimens for metastatic breast 
cancer are eligible. 
7. Participants must have fully recovered from the acute toxic effects of all prior treatment to 
grade 1 or less, except alopecia  which is allowed  
8. Participants must have a life expectancy ≥ 16 weeks. 
9. Participant must have Eastern Cooperative Oncology Group (ECOG) performance status ≤1 
(refer to Appendix C) 
10. Participant must consent to undergo a pre-treatment screening biopsy for enrollment and 
subsequent biomarker analyses. 
11. Participants must consent to undergo one mandatory on-study tumor biopsy following a 2-
week induction treatment of olaparib.  A second on-study biopsy at time of disease 
progression is optional but not mandatory. 
12. Participants must not have received previous treatment with PARP inhibitors, including 
olaparib 
13. Participants must have normal organ and bone marrow function measured within 28 days 
prior to administration of study treatment as defined below: 
a. Hemoglobin ≥ 10.0 g/dL   

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b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
c. Platelet count ≥ 100 x 109/L 
d. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
e. Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) 
/ Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 
x institutional upper limit of normal unless liver metastases are present in which case they 
must be ≤ 5x ULN 
f. Participants must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-
Gault equation or based on a 24-hour urine test: 
Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F) serum creatinine (mg/dL) x 
72; where F=0.85 for females and F=1 for males. 
 
14. Participants of childbearing potential must have a negative urine or serum pregnancy test 
within 28 days of study treatment and confirmed on Day 1 prior to receiving the first dose of 
study medication. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.   
15. Participants of childbearing potential agree to use adequate methods of contraception 
(Appendix D), upon signing of informed consent through:   
• 
6 months after the last dose with olaparib,  
• 
3 months after the last dose with durvalumab, 
• 
1 week after the last dose with selumetinib,  
• 
1 month after the last dose with capivasertib,  
• 
1 month after the last dose with ceralasertib.  
Participants of childbearing potential are those who are not proven postmenopausal. 
Postmenopausal is defined as: 
• 
Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments 
• 
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-
menopausal range for women under 50 
• 
Radiation-induced oophorectomy with last menses >1 year ago 
• 
Chemotherapy-induced menopause with >1 year interval since last menses 
• 
Surgical sterilization (bilateral oophorectomy or hysterectomy) 
 
16. Sperm-producing participants must use a condom during treatment and for 3 months after 
the last dose of olaparib when having sexual intercourse with a pregnant partner or with an 
individual of childbearing potential.  Partners of sperm-producing participants should also 
use a highly effective form of contraception ([see Appendix D for acceptable methods]) if 
they are of childbearing potential.  
a. Sperm-produding participants assigned to receive capivasertib must use a condom 
during treatment and for 4 months after the last dose of capivasertib when having sexual 
intercourse with a pregnant partner or with an individual of childbearing potential. 
 
 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 

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1. Any concurrent anticancer treatment.  
a. Individuals in the follow-up phase of a prior investigational study may participate as long 
as it has been 4 weeks since last dose of the previous investigational agent or device.  
b. Concurrent use of hormonal therapy for non cancer related conditions (e.g., hormone 
replacement therapy) is allowed. 
2. Participant’s with tumors showing androgen receptor (AR) ≥80% by immunohistochemistry 
are excluded.  
 
3. Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: 
adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, 
ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma.  Participants with 
a personal history of treated early stage breast cancer whose natural history or treatment 
does not have the potential to interfere with the safety or efficacy endpoints of the trial, per 
investigator assessment, are eligible. 
4. Participants with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML. 
5. Participant received prior anticancer therapy such as targeted therapies, or systemic 
chemotherapy or radiation (except for palliative reasons) within the past 3 weeks, or 5 half-
lives, whichever is shorter, prior to first day of treatment  
6. Participants with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  
a. Patients with brain metastases may participate provided they do not have symptomatic 
uncontrolled disease. The patient can receive a stable dose of corticosteroids before and 
during the study as long as these were started at least 4 weeks prior to treatment. (note: 
a scan to confirm the absence of brain metastases is not required). 
b. Patients with spinal cord compression are not eligible unless considered to have 
received definitive treatment for this and evidence of clinically stable disease for 28 
days. 
c. Patients with carcinomatous meningitis are not eligible.  
7. Concomitant use of known strong CYP3A inhibitors (e.g., ketoconazole, posaconazole), or  
strong CYP3A inducers (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, 
rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers 
(eg. bosentan, efavirenz, modafinil).  The required washout period prior to starting study 
intervention treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other 
agents. 
8. Major surgery within 4 weeks of starting study treatment and patients must have recovered 
from any effects of any major surgery. 
9. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT). 
10. Patients that are immunocompromised, including those with Human immunodeficiency virus 
(HIV) or acquired immunodeficiency syndrome (AIDS)-related illness are not eligible for 
participation. Note: HIV-infected participants on effective anti-retroviral therapy with 
undetectable viral load for ≥6 months are eligible for this trial provided that there is minimal 
interactions or overlapping toxicity of the antiretroviral therapy with their study intervention. 

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Refer to drug-specific exclusion criteria for additional considerations. 
11. Patients with known active hepatitis (i.e. Hepatitis B or C). Refer to drug-specific exclusion 
criteria for additional considerations. 
a. Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen 
(HBsAg) result.   
b. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody and absence of HBsAg) are eligible. 
c. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. Those with a positive HCV PCR will be 
excluded 
12. Participants unable to swallow orally administered medication and participants with 
gastrointestinal disorders likely to interfere with absorption of the study medication 
13. Participants with visceral crisis defined as severe organ dysfunction as assessed by signs and 
symptoms, laboratory studies, and rapid progression of disease173. 
14. Active infection requiring systemic antibiotic therapy. Participants requiring systemic 
antibiotics for infection must have completed therapy before treatment is initiated. 
15. Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection.  Examples include, but are 
not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial 
infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior 
vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution 
Computed Tomography (HRCT) scan or any psychiatric illness/social situation that prohibits 
obtaining informed consent. 
16. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by 
the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive 
heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or participants with 
congenital long QT syndrome 
17. Participants with a history of hypersensitivity reactions to study agent, olaparib, or its 
excipients. 
18. Participant is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment. 
19. Sperm-producing participants are prohibited from donating sperm upon signing of informed 
consent through: 
• 
3 months following last dose with olaparib,  
• 
4 months following last dose with capivasertib 
• 
6 months following last dose with ceralasertib 
20. Involvement in the planning and/or conduct of the study 
21. Judgment by the investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions, and requirements. 
 
4.2.1 DRUG-SPECIFIC EXCLUSION CRITERIA 
 

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The following criteria require consideration for participant eligibility to one or more of the 
available treatment arms.  Participant eligibility may be assessed at the time of initial screening 
or as part of the on-study assignment to a specific treatment arm.  
 
4.2.1.1 
Durvalumab Exclusion Criteria (if being considered for Arm 1) 
 
1. Participant has received prior immunotherapy with anti-PD-L1, including durvalumab anti-
PD-1, anti-CTLA4 or similar drugs in the metastatic setting. 
2. Participants may have received prior immunotherapy in the adjuvant setting, provided 
a. No documented disease progression on immunotherapy 
b. Treatment with immunotherapy was >1 year from enrollment on study 
3. Participant has evidence of interstitial lung disease or active non-infectious pneumonitis. 
4. Major surgery within 2 weeks of starting study treatment and participants must have 
recovered from any effects of any major surgery Note: Local surgery of isolated lesions for 
palliative intent is acceptable per investigator discretion.  
5. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local practice), 
hepatitis B (positive HBV surface antigen (HBsAg) result), hepatitis C, or  human 
immunodeficiency virus.  
a. Participants with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [anti-HBc] and absence of HBsAg) are eligible. 
b. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
c. Those with controlled human immunodeficiency virus (HIV) are eligible, provided that: 
i.  baseline CD4+ T-cell count is ≥200 cells/mm3, and 
ii. HIV plasma viral load is < 60 copies/ml 
6. History of active primary immunodeficiency 
7. Current or prior use of immunosuppressive medication within 14 days before the first dose of 
durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or 
an equivalent corticosteroid. The following are exceptions to this criterion: 
a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or 
its equivalent 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 
8. Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, 
etc.]). The following are exceptions to this criterion: 
a. Participants with vitiligo or alopecia 

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b. Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement  
c. Any chronic skin condition that does not require systemic therapy 
d. Participants without active disease in the last 5 years may be included but only after 
consultation with the study physician 
e. Participants with celiac disease controlled by diet alone 
9. History of allogenic bone marrow transplant or double umbilical cord blood transplantation  
10. Participants must not have received live vaccines within 30 days prior to the first dose of 
immunotherapy.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chickenpox, shingles, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines and are not allowed. Patients, if enrolled, should not receive a live vaccine while 
receiving immunotherapy and up to 30 days after the last dose of immunotherapy 
11. Participant has a history of hypersensitivity reactions to study agent, durvalumab, or its 
excipients. 
12. Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Investigator. 
13. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment 
with durvalumab may be included only after consultation with the Study Investigator. 
 
4.2.1.2 
Selumetinib Exclusion Criteria (if being considered for Arm 2) 
 
1. Prior treatment with a MEK, Ras or Raf inhibitor 
2. Participants with a history of hypersensitivity reactions to study agent, selumetinib, or its 
excipients. 
3. Current or past history of retinal pigment epithelial detachment (RPED)/central serous 
retinopathy (CSR) or retinal vein occlusion; or Intraocular pressure (IOP) > 21 mmHg or 
uncontrolled glaucoma (irrespective of IOP) 
4. HIV positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with selumetinib. 
5. Inability to swallow selumetinib capsules whole 
6.  Cardiac conditions as follows: 
a. Uncontrolled hypertension, defined as BP ≥ 150/95 mmHg despite medical therapy 
b. Acute coronary syndrome within 6 months prior to starting treatment 
c. Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy, or severe 
valvular heart disease (Appendix E) 
d. Uncontrolled Angina, defined as Canadian Cardiovascular Society grade II-IV despite 
medical therapy (Appendix F) 
7. Prior or current cardiomyopathy including but not limited to the following: 
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b. Known arrhythmogenic right ventricular cardiomyopathy 
c. Previous moderate or severe impairment of left ventricular systolic function (LVEF <45% 
on echocardiography or equivalent on MuGA) even if full recovery has occurred. 
d. Baseline Left ventricular ejection fraction (LVEF) below the  LLN or <55% measured by 
echocardiography or institution's LLN for MUGA 
e. Severe valvular heart disease 
f. Atrial fibrillation with a ventricular rate > 100 bpm on ECG at rest 
g. QTcF >450ms or other factors that increase the risk of QT prolongation 
 
4.2.1.3 
Capivasertib Exclusion Criteria (if being considered for Arm 3) 
 
1. Prior treatment with capivasertib or any of the following: 
a. AKT, PI3K, and/or mTOR inhibitors 
2. History of hypersensitivity to active or inactive excipients of capivasertib or drugs with a 
similar chemical structure or class to capivasertib 
3. Clinically significant abnormalities of glucose metabolism as defined by any of the 
following: 
a. Diabetes mellitus Type I or Type II requiring insulin treatment. 
b. HbA1c ≥8.0% (63.9 mmol/mol). 
4. Investigator judgment of 1 or more of the following:  
a. Mean resting corrected QT interval >470 ms, obtained from triplicate ECGs performed at 
screening. 
b. Medical history significant for arrhythmia (e.g., multifocal premature ventricular 
contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or 
requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation 
despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with 
atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may 
be permitted to enter the study. 
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as heart failure, hypokalaemia of Grade ≥1, potential for Torsades de Pointes, congenital 
long QT syndrome, family history of long QT syndrome or unexplained sudden death 
under 40 years of age in first-degree relative, history of QT prolongation associated with 
other medications that required discontinuation of the medication. See  for guidance on 
patients receiving any concomitant medication known to prolong the QT interval.  
d. Any clinically important abnormalities in rhythm, conduction or morphology of resting 
ECG (eg, complete left bundle branch block, third degree heart block) 
e. Experience of any of the following procedures or conditions in the preceding 6 months: 
coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina 
pectoris, congestive heart failure New York Heart Association (NYHA) grade ≥2  
f. Uncontrolled hypotension: systolic BP <90 mmHg and/or diastolic BP <50 mmHg  
g. Cardiac ejection fraction outside institutional range of normal or <50% (whichever is 
higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan if 

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an echocardiogram cannot be performed or is inconclusive). 
5. Inadequate bone marrow reserve or organ function as demonstrated by any of the following 
laboratory values at screening: 
a. Absolute neutrophil count <1.5 × 109/L 
b. Platelet count <100 × 109/L 
c. Hemoglobin <9 g/dL (<5.59 mmol/L). [Note: any blood transfusion must be >14 days 
prior to the determination of a hemoglobin ≥9 g/dL (≥5.59 mmol/L)] 
d. ALT and AST >2.5 × ULN if no demonstrable liver metastases or >5 × ULN in the 
presence of liver metastases. Elevated alkaline phosphatase (ALP) is not exclusionary if 
due to the presence of bone metastasis and liver function is otherwise considered 
adequate in the investigator’s judgement 
e. Total bilirubin >1.5 × ULN or >3×ULN in the presence of documented Gilbert’s syndrome 
(unconjugated hyperbilirubinemia).   
f. Creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault 
equation); confirmation of creatinine clearance is only required when creatinine is >1.5 × 
ULN 
6. Active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or 
hepatitis B virus core antibody, at screening.  
a. Patients who are hepatitis C antibody positive will need to have a negative PCR result 
before enrolment. Those who are hepatitis C PCR positive will be excluded. 
b. Patients who are hepatitis B virus surface antigen positive or hepatitis B PCR positive 
will be excluded. 
c. Patients who are anti-HBc antibody positive and who are surface antigen negative will 
need to have a negative PCR result before enrolment. 
7. HIV with a CD4+ T cell count <350 cells/μL or a history of an acquired immunodeficiency 
syndrome (AIDS)-defining opportunistic infection within the past 12 months. 
a. To ensure that effective anti-retroviral therapy (ART) is tolerated and that toxicities are 
not confused with investigational drug toxicities, trial participants should be on 
established ART for at least 4 weeks. 
b. Patients with HIV viral load > 400 copies/mL or those with a history of an AIDS-defining 
opportunistic infection will be excluded. 
c. Patients with CD4+ T-cell (CD4+) counts < 350 cells/uL will be excluded. 
i. Patients with a higher viral load or lower CD4+ count (< 350 cells/uL) may be 
considered for eligibility if the patient has a potentially curable malignancy or for 
interventions in a later stage of development that have demonstrated prior activity 
with a given cancer. 
8. Known to have active tuberculosis infection (clinical evaluation that may include history, 
physical examination and radiographic findings, or tuberculosis testing in line with 
institutional practice.  
9. Known history of drug or alcohol abuse within 12 months of screening. 
10. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal 

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diseases, inability to swallow the formulated product or previous significant bowel resection, 
or other condition that would preclude adequate absorption, distribution, metabolism, or 
excretion of capivasertib 
11. Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements. 
 
4.2.1.4 
Ceralasertib Exclusion Criteria (if being considered for Arm 4) 
 
1. Persisting (> 4 weeks) severe pancytopenia due to previous therapy rather than disease, 
defined as ANC < 0.5 x 109/L or platelets < 50 x 109/L 
2. Prior to study medication, the use of potent inducers or inhibitors of CYP3A are not 
permitted.  For subjects taking any of these drugs (examples provided in Appendix H) the 
required wash-out period before starting ceralasertib is five half-lives, except for St. John’s 
wort, which is 3 weeks. Subjects should also not received prescription or non-prescription 
drugs or other products known to be CYP3A4 and/or CYP2B6 substrates or CYP3A4 and/or 
CYP2B6 substrates with a narrow therapeutic index. Exposure of other drugs metabolised 
by CYP3A4 and/or CYP2B6 may be reduced and additional monitoring may be required. 
The use of herbal supplements or ‘folk remedies’ (and medications and foods that 
significantly modulate CYP3A activity) should be discouraged. Patients should stop using 
herbal medications 7 days prior to first dose of study treatment. 
3. History of hypersensitivity to active or inactive excipients of ceralasertib or drugs with a 
similar chemical structure or class to ceralasertib. 
4. Prior exposure to an ATR inhibitor 
5. A diagnosis of ataxia telangiectasia 
6. Time from prior treatment as follows: 
a. Cytotoxic chemotherapy, hormonal or non-hormonal targeted therapy within 21 days of 
Cycle 1 Day 1 is not permitted (a duration of 30 days or 5 half-lives (whichever is longer) 
is required for patients treated with non-cytotoxic drugs).  
b. The minimum washout period for immunotherapy is 42 days. 
c. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1 
(with the exception of patients receiving radiation to more than 30% of the bone marrow 
or with a wide field of radiation within 4 weeks of the first dose of study treatment). 
d. The patient can receive a stable dose of bisphosphonates or denosumab for bone 
metastases, before and during the study as long as these were started at least 5 days 
prior to the study treatment. 
e. Major surgical procedure (as defined by the investigator) within 28 days prior to the first 
dose of study agent: patients must have recovered from any effects of any major 
surgery. 
7. Impaired hepatic or renal function as demonstrated by any of the following laboratory 
values: 
a. Albumin < 33g/L (or outside of local laboratory reference ranges) 
b. ALP > 2.5 x ULN 
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investigating centre (i.e. Cockroft-Gault) 
d. Serum creatinine > 1.5 x ULN 
e. Hematuria: 3+ on microscopy or dipstick 
f. INR ≥ 1.5 or other evidence of impaired hepatic synthesis function 
8. Any of the following cardiac criteria currently or within the last 6 months of study entry (by 
New York Heart Association (NYHA) ≥ Class 2 heart failure, unstable angina, unstable 
cardiac arrhythmias or reduced LVEF<55%) 
9. Any of the following cardiac criteria: 
a. Mean resting corrected QT interval (QTc) >450 msec in males or >470 msec in females , 
obtained from 3 electrocardiograms (ECGs) 5-10 minutes apart  using the Fredericia 
formula  
b. Conduction abnormality not controlled with pacemaker or medication e.g. complete left 
bundle branch block, third degree heart block 
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as hypokalaemia, congenital long QT syndrome, immediate family history of long QT 
syndrome or unexplained sudden death under 40 years of age 
d. Unstable angina pectoris or acute myocardial infarction 
e. Congestive heart failure or known reduced LVEF < 55% 
f. Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or 
pre-syncopal or syncopal episodes, history of TIAs   
g. Patients with relative hypotension (< 100/60 mm Hg) or clinically relevant orthostatic 
hypotension, including a fall in blood pressure of >20mm Hg 
h. Uncontrolled hypertension (grade 2 or above) requiring clinical intervention 
 
 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
This study will be conducted in the US, and participants for this study will primarily be recruited 
from hematology and oncology practices within OHSU and affiliated community hematology and 
oncology (CHO) practices; as well as collaborating study sites (e.g., Oregon Oncology 
Specialists, University of Minnesota, Seattle Cancer Care Alliance).  Participants may be 
identified and referred to this study by their primary treating physician from within OHSU or 
CHO, collaborating study sites, or from the outside community.  Participants may be identified 
by a member of the participant’s treatment team, the PI, research team, or medical and surgical 
oncology clinics part of OHSU/CHO, or collaborating study sites.  As a member of the treatment 
team, the investigator(s) will screen their participant’s medical records for suitable research 
study participants and discuss the study and their potential for enrolling in the research study.  
Referral of potential participants to investigator(s) of this study is made as part of standard of 
care, with the referring physician seeking advice on the diagnosis, evaluation, and/or treatment 
of the participant’s malignancy.   
 
The investigators(s) may also screen the medical records of potential participants with whom 
the investigator does not have a treatment relationship.  This will be done for the limited purpose 
of identifying patients who would be eligible to enroll in the study and to record appropriate 
contact information in order to approach these potential individuals regarding the possibility of 

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participating in the study.  Participants may also initiate contact with the investigator through 
information of this study posted on the clinicaltrials.gov website. 
 
4.3.1 ACCRUAL ESTIMATES 
 
This is a multi-arm, phase II study with a target enrollment of up to 132 participants.  
 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic 
subset. No participant will be excluded from the study on the basis of gender, racial, or ethnic 
origin. Gender-nonconforming and gender-fluid individuals as members of the general 
population will also be recruited.  
 
The projected gender, racial, and ethnic composition of the study will comprise females because 
breast cancer largely or mostly affects this population.  The projected racial and ethnic 
composition of the female study participants will represent that of the state of Oregon, as well as 
that of the states of any participating collaborating study site. 
 
4.3.2 INCLUSION OF CHILDREN 
 
This protocol does not include children as the number of children with this type of cancer is 
limited. 
 
 
REGISTRATION PROCEDURES 
 
4.4.1 PARTICIPANT REGISTRATION 
 
4.4.1.1 
Local Registration 
 
Participants will be required to give written informed consent to participate in the study before 
any screening tests or evaluations are conducted that are not part of standard care. 
Registration from all consented participants must be entered into the OHSU electronic Clinical 
Research Management System (CRMS, e.g., eCRIS).  At a minimum, registration of OHSU 
participants will include: 
• 
Signed copies of the most recently Institutional Review Board (IRB)-approved, informed 
consent form and HIPAA authorization. 
• 
Investigator validation (signature and date) on participant’s inclusion and exclusion 
criteria  
 
4.4.1.2 
Multicenter Registration 
 
The OHSU coordinating center study team will manage the participant registration process. 
Investigators, or study team designee, at participating sites will identify eligible participants and 
send source documents that support eligibility to OHSU for review and verification before the 
participating site may enroll and treat the participant.  
 
The OHSU coordinating center team is responsible for verifying completeness of documents, 
entering registration information into the Knight CRMS, and assigning a study number/identifier 
for each individual participant.  The OHSU coordinating center will send an email to the 
participating site to indicate whether or not a participant is eligible and will assign a participant 
number/identifier.   
 
Registration at a participating research site will, at a minimum, include signed copies of the most 

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recent local IRB-approved, informed consent form and HIPAA authorization.  Upon consent, the 
participating study site must notify the OHSU coordinating site via breastclinicaltrials@ohsu.edu 
to register participants and obtain a participant identification number.  The participant 
identification numbers assigned by OHSU will begin with the site number and end with a 
sequential number. 
 
 
PARTICIPANT SCREENING AND ENROLLMENT 
 
In order to participate in this study, signed informed consent must be obtained from the 
participant.  The current IRB-approved informed consent must be signed and dated by each 
participant prior to undergoing any study procedures or before any prohibited medications are 
withheld from the participant in order to participate in this study.  
 
Screening will begin once the participant has provided written informed consent to participate in 
the study and ends on Day 1 of the study.  All screening and baseline evaluations will be 
performed during the screening phase (i.e., up to 28 days) before treatment when the study 
medication is initiated). Day 1 of the clinical trial will be when participants receive the first dose 
of on-study drug agent(s).  Total accrual of all participants is anticipated to take a total of 30 
months. 
 
 
PARTICIPANT WITHDRAWAL OR DISCONTINUATION 
 
Participants are free to withdraw consent and discontinue participation in the study at any time 
without prejudice to further treatment.  If a participant no longer wants to receive the on-study 
investigational drug regimen but is willing to participate in follow-up, the participant’s request 
should be honored, if possible.  No research biopsies will be performed.  If a biopsy is 
performed for other purposes, the participant’s permission will be sought to use excess tissue 
for banking and to support future unspecified research.  An individual participant will not receive 
any further investigational product if any of the following occur in the participant in question: 
 
• 
Withdrawal of consent or lost to follow-up. 
• 
Adverse event that, in the opinion of the investigator, contraindicates further dosing. 
• 
Participant is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a safety 
risk. 
• 
Pregnancy or intent to become pregnant. 
• 
Grade ≥ 3 infusion reaction. 
• 
Participant noncompliance that, in the opinion of the investigator, warrants withdrawal; e.g., 
refusal to adhere to scheduled visits. 
• 
Initiation of alternative anticancer therapy including another investigational agent 
• 
Requirement for concomitant use of a medication that is contraindicated (refer to Sections 
6.6 and 6.7) 
 
If a participant 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) 
• 
withdrawal of consent to the use of their study generated data 
• 
withdrawal to the use of any biological samples  
 

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No further participant contact should be made if the participant withdraws consent for 
participation in the study (including further follow-up). Information about the reason(s) for 
discontinuation and collection of any new or ongoing adverse events (AEs) should be collected 
at the time the participant withdraws consent.  
 
For all other reasons for discontinuation from the study treatment phase, the participant should 
return to the clinic for the end of treatment (EOT) visit according to Section 7.14. 
 
4.6.1 HANDLING PARTICIPANT WITHDRAWAL AND DISCONTINUATION 
 
Participants enrolled in this study that withdraws prior to initiating on-study treatment will be 
replaced. Participants that receive olaparib, but do not undergo planned treatment with the 
combination therapy (i.e., olaparib and durvalumab) will be replaced.  
 
 
OFF-STUDY CRITERIA 
 
Criteria that can take a participant off-study include: 
• 
Participant requests to be withdrawn from study without further follow-up, 
• 
Completed study follow-up period, 
• 
Progression of disease, 
• 
Death, 
• 
Screen failure, 
• 
Investigator’s discretion 
 
4.7.1 SCREEN FAILURES 
 
Any participant that has signed the consent form (for either screening or study participation) but 
does not meet the study eligibility criteria, or meets study eligibility criteria but terminates their 
participation prior to receiving study treatment, will be considered a screen failure.  The reason 
for screen failure should be captured in the database for each participant failing to meet the 
eligibility criteria.  
 
 
STUDY DISCONTINUATION 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to Sponsor, IRB, and other 
regulatory agencies (as required).  If the study is prematurely terminated or suspended, the 
Investigator will promptly inform the IRB and will provide the reason(s) for the termination or 
suspension. 
 
Reasons for terminating the study (or a single arm on the study) may include the following: 
• 
Incidence or severity of adverse events, in this or other studies, indicates a potential 
health hazard to participants. 
• 
Demonstration of efficacy that would warrant stopping. 
• 
Data that are not sufficiently complete and/or evaluable. 
• 
Investigator(s) do not adhere to the study protocol, or applicable regulatory guidelines in 
conducting the study.  
• 
Participant enrollment is unsatisfactory.  
• 
Submission of knowingly false information from the study site to regulatory authorities. 
• 
Upon instruction by local or other regulatory, or oversight authority.    
 

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Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the Sponsor, IRB and/or FDA. 
 

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5. INVESTIGATIONAL PRODUCT 
 
A list of the adverse events and potential risks associated with the investigational or other 
agents administered in this study can be found in the Adverse Events List (Section 9.4). 
 
 
OLAPARIB 
 
Olaparib (Lynparza®) is an inhibitor of poly (ADP-ribose) polymerases (PARP), which include 
PARP1, PARP2, and PARP3.  The PARP enzymes are involved in maintaining normal cellular 
homeostasis.  Refer to the olaparib investigator brochure for additional details.   
 
5.1.1 ACQUISITION 
 
The Investigational Products Supply section of AstraZeneca will supply olaparib tablets to the 
investigator. Following submission and approval of the required regulatory documents, a supply 
of olaparib may be ordered from AstraZeneca by completing a Drug Request Form.  
 
Allow 4 business days for shipment of drug from receipt of the Drug Request Form.  Drug is 
protocol specific, but not patient specific. There will be no weekend or holiday delivery of drugs. 
 
5.1.1.1 
Multicenter Acquisition 
 
Following participant registration, notify OHSU Research Pharmacy Services (RPS) at 
invdrugs@ohsu.edu to obtain drug.  Maintenance of drug accountability records is required for 
Olaparib.  The investigator, or a responsible party designated by the investigator, will maintain a 
careful record of the receipt, storage, disposition, and return of all drugs supplied for this study.   
 
5.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING  
 
Olaparib is a crystalline solid. Tablets are available for oral administration in 100 mg or 150 mg 
concentrations.  Inactive ingredients in the tablet core are: copovidone, mannitol, colloidal 
silicon dioxide, and sodium stearyl fumarate. The olaparib tablet coating consists of 
hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow, and ferrosoferric 
oxide (150 mg tablet only).   
 
a) Olaparib tablets (150mg) are green to green/grey, oval bi-convex, film-coated, and embossed 
with “OP150”. Olaparib 150mg is available in bottles of 60 or 120 tablets. 
 
b) Olaparib tablets (100mg) are yellow to dark yellow, oval bi-convex, film-coated, and 
embossed with “OP100”. Olaparib 100mg is available in bottles of 60 or 120 tablets. 
 
5.1.3 PRODUCT STORAGE AND STABILITY 
 
Store at 15°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59F to 86°F). Store 
in original bottle to protect from moisture.  
 
5.1.4 COMPATIBILITY 
 
Olaparib shows pH-independent low solubility of approximately 0.1 mg/ml across the 
physiological pH range. 
 

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5.1.5 HANDLING 
 
National Institute for Occupational Safety and Health (NIOSH) recommends the use of single 
gloves by anyone handling intact tablets or capsules or administering from a unit-dose package. 
 
5.1.6 PREPARATION 
 
None 
 
5.1.7 ADMINISTRATION 
 
Olaparib will be dispensed by the OHSU RPS or respective pharmacy services for each 
participating subsite. Olaparib (300mg) is to be administered orally twice daily, with or without 
food, for a total daily dose of 600 mg. The 100 mg tablet is available for dose reductions.  
 
5.1.8 SPECIAL CONSIDERATIONS FOR ADMINISTRATION  
 
Olaparib tablets should be taken at the same time each day, approximately 12 hours apart, with 
one glass of water.  The tablets should be swallowed whole and not chewed, crushed, 
dissolved, or divided. Olaparib tablets can be taken with or without food. If vomiting occurs 
shortly after the olaparib tablets are swallowed, the dose should only be replaced if all of the 
intact tablets can be seen and counted.  Should any participant enrolled on the study miss a 
scheduled dose for whatever reason (e.g., as a result of forgetting to take the tablets or 
vomiting), the participant will be allowed to take the scheduled dose up to a maximum of 2 hours 
after that scheduled dose time.  If greater than 2 hours after the scheduled dose time, the 
missed dose is not to be taken, and the participant should take their allotted dose at the next 
scheduled time. It is prohibited to consume grapefruit juice while on olaparib therapy. 
 
  
 
DURVALUMAB (MEDI4736) 
 
Durvalumab (IMFINZI™, MEDI4736) is a human immunoglobulin (Ig) G1 kappa (IgG1κ) 
monoclonal antibody (mAb) that blocks the interaction of PD-L1 with PD-1 on T-cells and CD80 
on immune cells.  Refer to the durvalumab investigator brochure for additional information.  
 
5.2.1 ACQUISITION 
 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab (MEDI4736) to the investigator as a 500-mg vial solution for infusion after dilution. 
Following submission and approval of the required regulatory documents, a supply of 
durvalumab may be ordered from AstraZeneca/MedImmune by completing a Drug Request 
Form.  
 
Allow 4 business days for shipment of drug from receipt of the Drug Request Form.  Drug is 
protocol specific, but not patient specific. There will be no weekend or holiday delivery of drugs. 
 
5.2.1.1 
Multicenter Acquisition 
 
Following participant registration, notify OHSU RPS at invdrugs@ohsu.edu to obtain drug.  
Maintenance of drug accountability records is required for Olaparib.  The investigator, or a 
responsible party designated by the investigator, will maintain a careful record of the receipt, 
storage, disposition, and return of all drugs supplied for this study.   
 

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5.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Durvalumab (MEDI4736) will be supplied as a 500-mg vial solution for infusion after 
dilution.  The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10.0 mL.  Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be 
kept in secondary packaging until use to prevent excessive light exposure.  
 
5.2.3 COMPATIBILITY 
 
Do not infuse other drugs via the same IV line as durvalumab 
 
5.2.4 HANDLING 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the study 
agent in a self-contained and protective environment. Clinical supplies must be stored in a 
secure, limited-access location under the storage conditions specified on the label. 
 
5.2.5 PREPARATION OF DURVALUMAB DOSES FOR ADMINISTRATION WITH AN IV BAG 
 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed: 
• 
24 hours at 2°C – 8°C (36°F – 46°F) 
• 
4 hours at room temperature 
If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hours (that is, the individual storage time limits are not additive). 
 
A dose of 1500mg (for participants >30kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with a 
0.2- or 0.22-μm in-line filter.  Add 30.0 mL of durvalumab (MEDI4736) (i.e., 1500mg of 
durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of 
the dose in the bag. Patients with ≤ 30kg weight should be dosed by weight 20mg/kg 
durvalumab Q4W. 
 
5.2.6 ADMINISTRATION 
 
Standard infusion time 1 hour, and modifications and/or interruptions to infusion time are 
allowed per local practice and institutional guidelines.  In the event that there are interruptions 
during infusion, the total allowed infusion time should not exceed 8 hours at room temperature. 
Administer infusion solution intravenously through an intravenous line containing a sterile, low-
protein binding 0.2 or 0.22 µm in-line filter.  Do not co-administer other drugs through the same 
infusion line. 
 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion 
set used after the contents of the IV bag are fully administered, or complete the infusion according 
to institutional policy to ensure the full dose is administered and document if the line was not 

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flushed. 
 
If either preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials.  Durvalumab (MEDI4736) does not contain preservatives, and any unused portion 
must be discarded.  
 
5.2.7 SPECIAL CONSIDERATION FOR ADMINISTRATION 
 
Durvalumab must be administered at room temperature by controlled infusion via an infusion 
pump into a peripheral vein or central line.  Prior to the start of the infusion, ensure that the bag 
contents are at room temperature to avoid an infusion reaction due to the administration of the 
solution at low temperatures. 
 
5.2.7.1 
Monitoring Durvalumab Dose Administration 
 
Participants who have an infusion-related reaction will be monitored before, during, and after the 
infusion with the assessment of vital signs at times specified in the Schedule of Events. In such 
cases, participants are monitored (e.g., pulse rate, blood pressure) every 30 minutes during the 
infusion period (including times where infusion rate is slowed or temporarily stopped). 
 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit participants to an intensive care unit if necessary. 
 
Please refer to 6.5.13 for the management of participants who experience an infusion reaction.   
 
 
CAPIVASERTIB 
 
Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 AKT isoforms that is 
under clinical development for the treatment for solid and hematological malignancies. Refer to 
the capivasertib investigator brochure for additional information.  
 
5.3.1 ACQUISITION 
 
The Investigational Products Supply section of AstraZeneca will supply capivasertib tablets to 
the investigator. Following submission and approval of the required regulatory documents, a 
supply of capivasertib may be ordered from AstraZeneca by completing a Drug Request Form.  
 
Allow 4 business days for shipment of drug from receipt of the Drug Request Form.  Drug is 
protocol specific, but not patient specific. There will be no weekend or holiday delivery of drugs. 
 
5.3.1.1 
Multicenter Acquisition 
 
Following participant registration, notify OHSU RPS at invdrugs@ohsu.edu to obtain drug.  
Maintenance of drug accountability records is required for capivasertib.  The investigator, or a 
responsible party designated by the investigator, will maintain a careful record of the receipt, 
storage, disposition, and return of all drugs supplied for this study.   
 

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5.3.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
The drug product is available for oral administration as beige film-coated tablets containing 160 
mg (round, 10 mm) or 200 mg (caplet shaped, 14.5 x 7.25 mm) of capivasertib.  The film-coated 
tablets contain capivasertib, microcrystalline cellulose, dibasic calcium phosphate, 
croscarmellose sodium, and magnesium stearate.  
 
5.3.3 PRODUCT STORAGE AND STABILITY 
 
The product should be stored in the pack provided and used according to the instructions on the 
label. 
 
5.3.4 HANDLING 
 
National Institute for Occupational Safety and Health (NIOSH) recommends the use of single 
gloves by anyone handling intact tablets or capsules or administering from a unit-dose package. 
 
5.3.5 PREPARATION 
 
None. 
 
5.3.6 ADMINISTRATION 
 
Capivasertib will be dispensed by the OHSU RPS or respective pharmacy services for each 
participating subsite. Capivasertib (400 mg) is to be administered orally twice daily, without food, 
for a total daily dose of 800 mg for 4 days, followed by a 3-day break in treatment. 
 
5.3.7 SPECIAL CONSIDERATIONS FOR ADMINISTRATION 
  
Capivasertib tablets should be taken at the same time each day, approximately 12 hours apart, 
with one glass of water.  The tablets should be swallowed whole and not chewed, crushed, 
dissolved, or divided. Capivasertib tablets should be taken without food, with participants 
preferably fasting approximately 2 hours before dosing and up to 1 hour after dosing. If vomiting 
occurs shortly after the capivasertib tablets are swallowed, the dose should only be replaced if 
all of the intact tablets can be seen and counted.  Should any participant enrolled on the study 
miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the tablets or 
vomiting), the participant will be allowed to take the scheduled dose up to a maximum of 2 hours 
after that scheduled dose time.  If greater than 2 hours after the scheduled dose time, the 
missed dose is not to be taken, and the participant should take their allotted dose at the next 
scheduled time. 
 
 
SELUMETINIB 
 
Selumetinib is a potent inhibitor of MEK1/2.  Refer to the selumetinib investigator brochure for 
additional information. 
 
5.4.1 ACQUISITION 
 
AstraZeneca will supply selumetinib  capsules to the investigator. Following submission and 
approval of the required regulatory documents, a supply of selumetinib may be ordered from 
AstraZeneca by completing a Drug Request Form.  

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Allow 4 business days for shipment of drug from receipt of the Drug Request Form.  Drug is 
protocol specific, but not patient specific. There will be no weekend or holiday delivery of drugs. 
 
5.4.1.1 
Multicenter Acquisition 
 
Following participant registration, notify OHSU RPS at invdrugs@ohsu.edu to obtain drug.  
Maintenance of drug accountability records is required for selumetinib.  The investigator, or a 
responsible party designated by the investigator, will maintain a careful record of the receipt, 
storage, disposition, and return of all drugs supplied for this study. 
 
5.4.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
The drug product is available as a capsule for oral administration. The drug product may be 
provided in 10 mg or 25 mg capsule forms.  The capsules contain selumetinib and Vitamin E 
polyethylene glycol succinate. The 10 mg capsule shell contains: hypromellose, carrageenan, 
potassium chloride, titanium dioxide, carnauba wax, and purified water.  The 10 mg capsule 
printing ink contains: shellac, iron oxide black, propylene glycol, and ammonium hydroxide.  The 
25 mg capsule shell contains: hypromellose, carrageenan, potassium chloride, titanium dioxide, 
FD&C blue 2, ferric oxide yellow, purified water, carnauba wax and/or corn starch.  The 25 mg 
printing ink contains: ferric oxide red, ferric oxide yellow, FD&C Blue 2 aluminum lake, carnauba 
wax, shellac, glyceryl monooleate. 
 
5.4.3 PRODUCT STORAGE AND STABILITY 
 
The capsules should be stored in their original packaging until use. For further information, 
investigators should refer to the investigational product label. 
 
5.4.4 HANDLING 
 
National Institute for Occupational Safety and Health (NIOSH) recommends the use of single 
gloves by anyone handling intact capsules or administering from a unit-dose package. 
 
5.4.5 PREPARATION 
 
None 
 
5.4.6 ADMINISTRATION 
 
Selumetinib will be dispensed by the OHSU RPS or respective pharmacy services for each 
participating subsite.  Selumetinib is to be administered orally twice daily, without food, that is 
based on body surface area (BSA) dosing per Table 15.   
 
5.4.7 SPECIAL CONSIDERATIONS FOR ADMINISTRATION 
 
Selumetinib capsules should be taken at the same time each day, approximately 12 hours 
apart, with one glass of water.  The capsules should be swallowed whole and not chewed, 
crushed, dissolved, or opened.  Selumetinib capsules should be taken without food, with 
participants preferably fasting approximately 2 hours before dosing and up to 1 hour after 
dosing.  If vomiting occurs shortly after the selumetinib capsules are swallowed, no additional 
dose should be taken, but instead, continue with the next scheduled dose.  Should any 

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participant enrolled on the study miss a scheduled dose for whatever reason (e.g., as a result of 
forgetting to take the capsules), the participant will be allowed to take the scheduled dose up to 
a maximum of 6 hours after that scheduled dose time.  If greater than 6 hours after the 
scheduled dose time, the missed dose is not to be taken, and the participant should take their 
allotted dose at the next scheduled time. 
 
 
CERALASERTIB 
 
Ceralasertib is a potent, selective inhibitor of the serine (Ser)/threonine (Thr)-specific protein 
kinase, ATR, as well as good selectivity against other phosphatidylinositol 3-kinase-related 
kinase (PIKK) family members.  Refer to the ceralasertib investigator brochure for additional 
information. 
 
5.5.1 ACQUISITION 
 
AstraZeneca will supply ceralasertib tablets to the investigator. Following submission and 
approval of the required regulatory documents, a supply of ceralasertib may be ordered from 
AstraZeneca by completing a Drug Request Form.  
 
Allow 8 weeks for shipment of drug from receipt of the Drug Request Form.  Drug is protocol 
specific, but not patient specific. There will be no weekend or holiday delivery of drugs. 
 
5.5.1.1 
Multicenter Acquisition 
 
Following participant registration, notify OHSU RPS at invdrugs@ohsu.edu to obtain drug.  
Maintenance of drug accountability records is required for ceralasertib.  The investigator, or a 
responsible party designated by the investigator, will maintain a careful record of the receipt, 
storage, disposition, and return of all drugs supplied for this study.   
 
5.5.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Ceralasertib is a crystalline powder that is presented as film-coated tablets containing 20 mg or 
80 mg of the drug product.  Ceralasertib coated tablets contain a blend of ceralasertib, mannitol, 
microcrystalline cellulose, sodium starch glycolate, magnesium stearate, and silicon dioxide. 
 
5.5.3 PRODUCT STORAGE AND STABILITY 
 
The product should be stored in the pack provided and used according to the instructions on 
the label. 
 
5.5.4 COMPATIBILITY 
 
Ceralasertib displays classic pH-dependent solubility behavior in the intestinal pH range, with a 
solubility of 26.6 mg/mL at pH 2.5 and 0.49 mg/mL at pH 6.5. 
 
5.5.5 HANDLING 
 
National Institute for Occupational Safety and Health (NIOSH) recommends the use of single 
gloves by anyone handling intact tablets . 
 

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5.5.6 PREPARATION 
 
None 
 
5.5.7 ADMINISTRATION 
 
Ceralasertib will be dispensed by the OHSU RPS or respective pharmacy services for each 
participating subsite.  Ceralasertib (240 mg) is to be administered orally twice daily for days 1-14 
of every 28 day cycle.  
 
5.5.8 SPECIAL CONSIDERATIONS FOR ADMINISTRATION 
 
Ceralasertib tablets should be taken at approximately the same time each day, with one glass of 
water.  The tablets should be swallowed whole and not chewed, crushed, dissolved, or divided. 
Ceralasertib tablets should be taken after fasting for 2 hours before dosing and for an additional 
1 hour after the dose has been administered.  If vomiting occurs shortly after the ceralasertib 
tablets are swallowed, the dose should only be replaced if all of the intact tablets can be seen 
and counted.  Should any participant enrolled on the study miss a scheduled dose for whatever 
reason (e.g., as a result of forgetting to take the tablets or vomiting), the participant will be 
allowed to take the scheduled dose up to a maximum of 2 hours after that scheduled dose time.  
If greater than 2 hours after the scheduled dose time, the missed dose is not to be taken, and 
the participant should take their allotted dose at the next scheduled time. It is prohibited to 
consume grapefruit juice while on ceralasertib therapy. 
 
 
ACCOUNTABILITY (ALL INVESTIGATIONAL PRODUCTS) 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful 
record of the inventory and disposition of the study agent. (See the NCI Investigator’s Handbook 
for Procedures for Drug Accountability and Storage).   
 
Responsibility for drug accountability at the study site rests with the Investigator; however, the 
Investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee. Inventory and accountability records must be maintained and readily available for 
inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities or other oversight bodies. 
 
The Investigator or designee will collect and retain all used, unused, and partially used 
containers of study medication until full accounting has been completed. The Investigator or 
designee must maintain records that document: 
• Investigational product delivery to the study site. 
• The inventory at the site. 
• Use by each participant including pill/unit counts from each supply dispensed. 
• Return of investigational product to the Investigator or designee. 
• Destruction or return of investigational product for final disposal. 
 
These records should include dates, quantities, batch/serial numbers (if available), and the 
unique code numbers (if available) assigned to the investigational product and study 
participants. 
 
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will also maintain records adequately documenting that the participants were provided the 
correct study medication specified.  Completed accountability records will be archived by the 
 
 
DESTRUCTION AND RETURN (ALL INVESTIGATIONAL PRODUCTS) 
 
At the completion of the study, the Investigator or designee will oversee the destruction of study 
agents per local institutional guidelines.  

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6. TREATMENT PLAN 
 
 
DOSAGE AND ADMINISTRATION 
 
Treatment will be administered on an out-patient basis, with 28 consecutive days defined as a 
treatment cycle.  Reported adverse events and potential risks are described in Section 9.4, 
Adverse Event List(s).  Appropriate dose modifications are described in Section 6.2.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 
 
 
6.1.1 CYCLE 1 – LEAD IN MONOTHERAPY REGIMEN 
 
Participants will receive olaparib (300 mg) orally, twice a day (i.e., every 12 hours) starting on 
Day 1 for a total of 28 days  (i.e., 1 cycle).  Halfway through this 4-week induction treatment 
period, participants will undergo an on-study tumor biopsy (i.e., Cycle 1, Day 14 ± 7 days).  After 
the induction treatment period, participants will receive olaparib in combination with the 
assigned medication for each treatment arm or ceralasertib monotherapy (Section 6.1.2).  
 
6.1.2 CYCLE 2 TO CYCLE 13 – COMBINATION THERAPIES AND CERALASERTIB 
MONOTHERAPY 
 
Based on selection criteria guidelines described in Appendix A, participants will be assigned to 
one of 4 treatment arms comprising either olaparib (300 mg PO BID) administered in 
combination with durvalumab, capivasertib, or selumetinib, or ceralasertib monotherapy.   
 
6.1.2.1 
Arm 1 – Olaparib and Durvalumab 
 
Olaparib (300 mg, PO, BID) will be administered at the same specified dose and timing for 
another 12 cycles (i.e., for a total of 13 on-study treatment cycles).  Starting on Cycle 2, 
participants in Arm 1 will concomitantly receive durvalumab (1500 mg IV) on Day 1 of each 28-
day cycle for a total of 12 cycles. 
 
6.1.2.2 
Arm 2 – Olaparib and Selumetinib 
 
Olaparib (300 mg, PO, BID) will be administered at the same specified dose and timing for 
another 12 cycles (i.e., for a total of 13 on-study treatment cycles).  Starting on Cycle 2, 
Table 3. Regimen Description 
Agent 
Premedication
; Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Olaparib 
 
300 mg 
PO 
BID 
28 days 
Durvalumab 
1-2 mg/kg/day 
prednisone or 
equivalent 
1500 mg 
IV over 
1hr* 
Q4wk 
28 days 
Capivasertib 
 
400 mg 
PO 
Intermittent dosing of 4 
days BID on,3 days off 
28 days 
Selumetinib 
 
BSA dosing 
per Table 15 
PO 
BID 
28 days 
Ceralasertib 
 
240 mg 
PO 
BID for days 1 to 14 
28 days 

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participants will concomitantly receive selumetinib (BSA dosing per Table 15) to be 
administered continuously for 28 days, for a total of 12 cycles. 
 
6.1.2.3 
Arm 3 – Olaparib and Capivasertib 
 
Olaparib (300 mg, PO, BID) will be administered at the same specified dose and timing for 
another 12 cycles (i.e., for a total of 13 on-study treatment cycles).  Starting on Cycle 2, 
participants will concomitantly receive capivasertib (400 mg PO, BID) for 4 days, followed by a 
3-day break in treatment.  This alternating treatment regimen will be repeated throughout each 
28-day cycle for a total of 12 cycles. 
 
6.1.2.4 
Arm 4 – Ceralasertib monotherapy 
 
Starting on Cycle 2, participants will receive ceralasertib (240 mg PO BID) to be administered 
on Day 1 through 14 of each 28-day cycle, for a total of 12 cycles. 
 
Participants in any of the available treatment arms may continue to receive their assigned 
therapy beyond the planned 13 cycles in the absence of disease progression or unacceptable 
toxicity. Participants in Arm 1 suspected of pseudoprogrsison could be treated beyond 
suspected disease progression at the investigator’s discretion if they are deriving apparent 
clinical benefit and tolerating treatment.  Participants with confirmed disease progression (per 
RECIST v1.1 for Arms 2-4, or irRECIST for Arm 1) will be offered physician’s choice therapy per 
institutional guidelines.  In this case, participants are considered off-protocol directed therapy, 
but be followed for disease status and survival outcomes. 
 
 
DOSING DELAYS  
 
In general, dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons (i.e., elective surgery, unrelated medical events, vacation, and holidays) not related to 
study therapy.  Participants should be placed back on study therapy within 4 weeks of the 
scheduled interruption unless otherwise discussed with the investigator. The reason for 
interruption should be documented in the participant's study record. 
 
6.2.1 OLAPARIB 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should a participant miss a 
scheduled dose for whatever reason (e.g., forgot to take the tablets or vomiting), the participant 
will be allowed to take the scheduled dose up to a maximum of 2 hours after that scheduled 
dose time.  If greater than 2 hours after the scheduled dose time, the missed dose is not to be 
taken, and the participant should take their allotted dose at the next scheduled time. 
 
6.2.2 DURVALUMAB 
 
Durvalumab dosing can be delayed up to 3 cycles, or 12 weeks, due to toxicity, for up to two 
occurrences.  In the event of a third occurrence of a toxicity requiring a dosing delay, study 
therapy will be permanently discontinued. 
 
6.2.3 CAPIVASERTIB 
 
Treatment with capivasertib may be temporarily interrupted for toxicities, as described in Section 

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6.3.4. 
 
6.2.4 SELUMETINIB 
 
Any toxicity observed during the course of the study may be managed by an interruption or dose 
reductions of selumetinib described in Section 6.3.5. 
 
6.2.5 CERALASERTIB 
 
Any toxicity observed during the course of the study may be managed by an interruption or dose 
reductions of ceralasertib described in Section 6.3.6. 
 
 
DOSE MODIFICATION GUIDELINES 
 
As applicable, and per the medical judgement of the treating physician, cases of overlapping 
hematological and non-hematological toxicities for all the olaparib treatment combinations (i.e., 
Arms 1, 2, and 3), may be managed by dose modifications to olaparib and/or the respectively 
assigned combination study agent (i.e., durvalumab, selumetinib, or capivasertib).  
 
6.3.1 MANAGEMENT OF OLAPARIB-RELATED TOXICITIES 
 
Table 4. Dose reductions for olaparib treatment 
Initial Dose 
Following re-challenge post interruption: 
Dose reduction 1 
Dose reduction 2 
300mg twice daily 
250mg twice daily 
200mg twice daily 
 
Table 5. Dose reduction for olaparib treatment if participant develops moderate renal 
impairment  
Initial Dose 
Moderate renal impairment (calculated creatinine clearance by 
Cockcroft -Gault equation or based on a 24-hour urine test between 
31 and 50 ml/min): Dose reduction  
300 mg twice daily 
200 mg twice daily 
 
Table 6. Dose reductions for study treatment if participant has to start taking a strong or 
moderate CYP3A inhibitor 
Initial Dose 
Strong CYP3A inhibitor 
Moderate CYP3A inhibitor 
300 mg twice daily 
100 mg twice daily 
150 mg twice daily 
 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided (see Section 6.6). 
When dose reduction is necessary, participants will take one 150 mg tablet and one 100 mg 
tablet twice daily or two x 100 mg tablet twice daily, or one 150 mg tablet twice daily or one 100 
mg tablet twice daily (see Section 6.6). 
 
Any toxicity observed during the course of the study could be managed by an interruption of the 
study drug treatment or dose reductions.  Repeat dose interruptions are allowed as required, for 
a maximum of 4 weeks on each occasion. If the interruption is any longer, the study team must 

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be informed. Olaparib can be dose reduced to 250 mg twice daily as a first step and to 200 mg 
twice daily as a second step.  If the reduced dose of 200 mg twice daily is not tolerable, no 
further dose reductions are permitted, and the participant’s on-study treatment should be 
discontinued.  Once dose is reduced, escalation is not permitted (except following concomitant 
treatment with CYP3A4 inhibitors (refer to Section 6.6.1). 
 
6.3.1.1 
Management of hematological toxicity – Anemia 
 
Table 7. Management of anemia 
Hemoglobin (Hb) 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
 
Give appropriate supportive treatment and 
investigate causality. 
 
First occurrence: 
 
Physician judgment to continue olaparib with 
supportive treatment (e.g., transfusion) or interrupt 
dose for a maximum of 4 weeks. Study treatment 
can be restarted if Hb has recovered to > 9g/dl. 
 
Subsequent occurrences: 
 
If repeat Hb< 10 but ≥ 9 g/dl investigator 
judgement to continue olaparib with supportive 
treatment (e.g., transfusion) or dose interrupt (for 
max of 4 weeks) until Hb ≥ 10 g/dl and upon 
recovery dose reduction may be considered (to 
250 mg twice daily as a first step and to 200 mg 
twice daily as a second step). 
 
If Hb< 9 but ≥ 8 g/dl, dose interrupt (for max of 4 
weeks) until Hb ≥ 9 g/dl and upon recovery dose 
reduction may be considered (to 250 mg twice 
daily as a first step and to 200 mg twice daily as 
a second step). 
Hb < 8 g/dl 
(CTCAE Grade 3) 
 
Give appropriate supportive treatment (e.g., 
transfusion) and investigate causality. 
 
Interrupt olaparib for a maximum of 4 weeks until 
improved to Hb ≥ 9 g/dl. 
 
Upon recovery, dose reduce to 250 mg twice daily 
as a first step and to 200 mg twice daily as a 
second step in the case of repeat Hb decrease. 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases, the 
management of anemia may require blood transfusions. For cases where participants develop 
prolonged hematological toxicity (≥2 week interruption/delay in study treatment due to CTC 
grade 3 or worse anemia and/or development of blood transfusion dependence), refer to 

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guidance later in this section for the management of this.  
 
6.3.1.2 
Management of hematological toxicity – neutropenia, leukopenia and 
thrombocytopenia 
 
Table 8. Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity  
Olaparib dose adjustment 
CTCAE Grade 1-2 
Investigator judgment to continue treatment or if dose interruption, 
this should be for a maximum of 4 weeks; appropriate supportive 
treatment and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 1 or better for a 
maximum of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose 
reduce olaparib to 250 mg twice daily as a first step and 200 mg 
twice daily as a second step 
 
Adverse events of neutropenia and leukopenia should be managed as deemed appropriate by 
the investigator or physician with close follow up and interruption of program drug if CTCAE 
grade 3 or worse neutropenia occurs. 
 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a participant develops febrile neutropenia, olaparib should be stopped, and 
appropriate management including G-CSF should be given according to institutional guidelines.   
 
**Note that G-CSF should not be used within at least 24 h (7 days for pegylated G-CSF) of the 
last dose of olaparib unless absolutely necessary.** 
 
Platelet transfusions, if indicated, should be done according to institutional guidelines. 
 
In cases where participants develop prolonged hematological toxicity (≥2 week interruption or 
delay in treatment due to CTCAE grade 3 or worse), refer to Section 6.3.1.3. 
 
6.3.1.3 
Management of prolonged hematological toxicities  
 
If a participant develops prolonged hematological toxicity such as: 
• 
≥2 week interruption/delay in olaparib treatment due to CTCAE grade 3 or worse anemia 
and/or development of blood transfusion dependence 
• 
≥2 week interruption/delay in olaparib treatment due to CTCAE grade 3 or worse 
neutropenia (ANC < 1 x 109/L) 
• 
≥2 week interruption/delay in program treatment due to CTCAE grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 50 x 
109/L) 
 
Monitor weekly differential blood counts, including reticulocytes and peripheral blood smear.  If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
participant should be referred to a hematologist for further investigations.  Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to institutional 
guidelines.  Olaparib should be discontinued if blood counts do not recover to CTCAE grade 1 
or better within 4 weeks of dose interruption. 
 
The development of a confirmed myelodysplastic syndrome or other clonal blood disorder 

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should be reported as an SAE and full reports must be provided by the investigator to sponsor 
and AstraZeneca Patient Safety.  Olaparib should be discontinued in the event of a participant 
having a confirmed diagnosis of myelodysplastic syndrome and/or acute myeloid leukemia. 
 
6.3.1.4 
Management of non-hematological toxicity 
 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each 
occasion.  If the interruption is any longer than this the OHSU study team must be informed.    
Where toxicity reoccurs following re-challenge with olaparib, and where further dose 
interruptions are considered inadequate for management of toxicity, then the participant should 
be considered for dose reduction or must permanently discontinue on-study treatment. 
 
On-study treatment of olaparib can be dose reduced to 250 mg BID as a first step and to 200 
mg BID as a second step.  Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 
adverse event occurs, which the investigator or treating physician considers to be related to 
administration of olaparib.  
 
6.3.1.5 
Management of new or worsening pulmonary symptoms 
 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in olaparib dosing is recommended, and further 
diagnostic workup (including a high-resolution CT scan) should be performed to exclude 
pneumonitis.  Following investigation, if no evidence of abnormality is observed on CT imaging 
and symptoms resolve, then olaparib can be restarted, if deemed appropriate by the site 
investigator.  Identification of significant pulmonary abnormalities need to be discussed with the 
site investigator. 
 
6.3.1.6 
Management of Nausea and Vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment. These 
events are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent, and 
manageable on continued treatment. The first onset generally occurs in the first month of 
treatment for nausea and within the first 6 months of treatment for vomiting. For nausea, the 
incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; 
however, participants should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local treatment practice 
guidelines.  Alternatively, olaparib tablets can be taken with a light meal/snack (i.e., 2 pieces of 
toast or a couple of biscuits). 
 
As per international guidance on anti-emetic use in cancer participants (ESMO, NCCN), 
generally, a single agent antiemetic should be considered (e.g., dopamine receptor antagonist, 
antihistamines or dexamethasone). 
 
6.3.1.7 
Interruptions for intercurrent non-toxicity related events 
 
Olaparib dose interruption for conditions other than toxicity resolution should be kept as short as 
possible. If a participant cannot restart on-study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 

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discussed with the investigator. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
Reductions or interruptions are to be recorded in the eCRF. 
 
Olaparib treatment should be stopped at least 3 days prior to planned surgery. After surgery, 
on-study treatment can be restarted when the wound has healed.  No stoppage of treatment is 
required for any needle biopsy procedure174. 
 
Study treatment should be discontinued for a minimum of 3 days before a participant undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
 
Because the AEs related to olaparib may include asthenia, fatigue, and dizziness, participants 
should be advised to use caution while driving or using machinery if these symptoms occur.  
 
6.3.2 RENAL IMPAIRMENT 
 
If subsequent to study entry and while still on study therapy, a participant’s estimated CrCl falls 
below the threshold for study inclusion (≥51 ml/min), retesting should be performed promptly.  
A dose reduction is recommended for participants who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation or based on a 24-hour urine test of 
between 31 and 50 ml/min) for any reason during the course of the study: the dose of olaparib 
should be reduced to 200 mg twice daily. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted. 
Olaparib has not been studied in participants with severe renal impairment (creatinine clearance 
≤ 30 ml/min) or end-stage renal disease; if participants develop severe impairment or end-stage 
disease, it is recommended that olaparib be discontinued. 
 
6.3.3 MANAGEMENT OF DURVALUMAB-RELATED TOXICITIES 
 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab are provided in the separately provided 
durvalumab Toxicity Management Guidelines (TMG).  
 
Participants should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the immune-mediated adverse 
events (imAE). Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be 
used to support an imAE diagnosis. In the absence of a clear alternative etiology, events should 
be considered potentially immune-related. 
 
Refer to the separately provided TMG for general dose modification guidelines associated with 
immune-related reactions.  In general, based on the severity of the adverse reactions, 
durvalumab should be withheld and corticosteroids administered.  Increasing the dose of 
corticosteroids and/or using other systemic immunosuppressants may be warranted (at the 
discretion of the treating physician) if there is worsening or no improvement.  Upon improvement 
to ≤Grade 1, corticosteroid taper should be initiated and continued over at least 1 month.  Refer 
to Table 9 for the management of non-immune-mediated adverse reactions. 

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Table 9. Recommended Non–Immune-Mediated Reactions treatment modifications*  
Severity Grade of Event 
(NCI CTCAE v. 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not 
required for AEs not deemed to be 
related to study treatment (i.e., 
events due to underlying disease) or 
for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per 
institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per 
institutional standard. 
Grade 2 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
Treat accordingly, as per 
institutional standard. 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 
within 7 days or resolve to ≤Grade 1 
or baseline within 14 days, resume 
study drug/study regimen 
administration. Otherwise, 
discontinue study drug/study 
regimen. 
Treat accordingly, as per 
institutional standard. 
Grade 4 
 
Discontinue study drug/study 
regimen (Note: For Grade 4 labs, 
decision to discontinue should be 
based on accompanying clinical 
signs/symptoms, the Investigator’s 
clinical judgment, and consultation 
with the Sponsor.). 
Treat accordingly, as per 
institutional standard. 
 
6.3.3.1 
Infusion-related reaction 
 
Participants who have an infusion-related reaction will be monitored before, during, and after the 
infusion with the assessment of vital signs at times specified in Section 7.14, Schedule of 
Events. Participants are monitored (pulse rate, blood pressure) every 30 minutes during the 
infusion period (including times where infusion rate is slowed or temporarily stopped). Refer to 
separately provided TMG for general dose modification guidelines associated with infusion-
related reactions.  
 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For participants with a ≤Grade 2 infusion-
related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. 
 
If the infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued.  

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The standard infusion time is one hour; however, if there are interruptions during infusion, the 
total allowed time from infusion start to completion of infusion should not exceed 8 hours at 
room temperature.   
 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit participants to an intensive care unit if necessary. 
 
6.3.4 MANAGEMENT OF CAPIVASERTIB-RELATED TOXICITIES 
 
6.3.4.1 
Dose Modifications due to general capivasertib-related toxicities  
 
When intervention-related toxicities are observed, the investigator will decide, on a case by case 
basis, whether dose discontinuation, interruption, delay or reduction of therapy is most 
appropriate. 
 
Appropriate and optimal intervention of the toxicity is assumed prior to considering dose 
modifications. The study physician may be consulted prior to discontinuation of study drug due 
to toxicities.  The following should be considered: 
• Severity of study intervention related toxicity and the number of concurrent adverse events 
• Likely causality to study agents based on previous clinical experience and published safety 
data (refer to the capivasertib and olaparib IBs, respectively) 
Intervention with capivasertib should be temporarily interrupted for any intolerable AE 
regardless of grade or for any AE grade ≥3, where the investigator considers the AE of concern 
to be specifically associated with capivasertib (not attributable to the disease under investigation 
or olaparib).  A maximum of 2 dose reduction steps are permitted (Table 10).  If, after the 
second dose reduction treatment is not tolerated, no further dose reduction is allowed, and 
study treatment should be discontinued. Dose modification guidelines for capivasertib-related 
toxicities are shown in Table 11.   
 
Table 10. Dose reductions for capivasertib treatment 
Initial Dose 
Following re-challenge post interruption: 
Dose reduction 1 
Dose reduction 2 
400 mg twice daily  
(4 days on/3 days off) 
320 mg twice daily  
(4 days on/ 3 days off) 
200 mg twice daily  
(4 days on/ 3 days off) 
 
Table 11. Dose modifications for general capivasertib-related toxicities  
Severity Grade of Event 
(NCI CTCAE v. 5.0) 
Toxicity Management 
Grade 1 or 2 clinically 
significant  
Hold dosing and follow algorithm below, depending on outcome 
• 
Resolves to baseline or 
clinically tolerable 
within 21 days of onset 
• 
Resume dosing at same dose or one reduced dose level as 
clinically appropriate (Table 10) 

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Table 11. Dose modifications for general capivasertib-related toxicities  
Severity Grade of Event 
(NCI CTCAE v. 5.0) 
Toxicity Management 
• 
Does not resolvea 
within 21 days of onset 
• 
Discontinue study drug and observe patient until resolution 
Grade ≥3 
Hold dosing and follow algorithm bellow, depending on outcome  
• 
Grade ≥3 toxicity for 
≤21 days and resolves 
to ≤Grade 2or baseline 
within 21 days of onset  
• 
Resume dosing at same dose or one reduced dose level as 
clinically appropriate (Table 10) 
• 
Grade ≥3 toxicity for 
>21 days 
• 
Discontinue study drug and observe patient until resolution 
 
6.3.4.2 
Hyperglycemia 
 
These are general recommendations; therefore, due consideration should be given to baseline 
values and fasting conditions (and time since food if applicable) when interpreting glucose 
results.  In diabetic patients, it may be beneficial to rule out concomitant aetiologies that could 
be associated with hyperglycaemia (e.g. infections, dehydration, vascular events, 
glucocorticoids).  Participants should be made aware of symptoms of hyperglycaemia (eg, 
polydipsia and polyuria).  Dose modification guidelines for capivasertib-related hyperglycemia 
are shown in Table 12.   
 
In addition, for all grades, patients may receive education on lifestyle changes (eg, a diabetic 
diet) and consider beginning home glucose monitoring (eg, fasting self-blood glucose monitoring 
[SBGM] once-daily) at the discretion of the investigator.  If glucose home monitoring is 
instituted, the capivasertib treatment decision should be based on the morning fasting glucose 
value obtained prior to the dose of capivasertib.  
 
It is recommended that approaches to the management of capivasertib-induced hyperglycaemia 
include advice from a diabetologist where appropriate (eg, diabetic patients). Metformin is 
currently the preferred oral antidiabetic recommended for the management of hyperglycaemia 
occurring in patients participating in studies of capivasertib (see below for further guidance). If a 
second agent is required, consideration should be given to the intermittent schedule of 
capivasertib and the pattern of glucose changes (eg. sulphonylureas should be avoided due to 
their risk of hypoglycaemia secondary to their mechanism of action).    
 
Table 12. Dose modifications for capivasertib-related hyperglycemia 
NCI CTCAE v5 Toxicity Grade 
Management 
Grade 1 
Abnormal glucose above baseline 
with no medical intervention 
Maintain same capivasertib dose level.  

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Table 12. Dose modifications for capivasertib-related hyperglycemia 
NCI CTCAE v5 Toxicity Grade 
Management 
Grade 2  
Change in daily management 
from baseline for a diabetic; oral 
antiglycemic agent initiated; 
workup for diabetes 
 
Asymptomatic 
• 
Maintain same capivasertib dose level. 
• 
Treatment as per local guidelines, consider the use 
of oral antidiabetic (eg, metformin) on capivasertib 
dosing days [see further guidance on choice of 
antidiabetic agents on text above and below the 
table]. 
 
Symptomatic (Appropriate clinical management as per 
local guidelines) 
• 
Interrupt capivasertib until resolution of symptoms 
and fasting blood glucose is ≤ 160 mg/dL or ≤8.9 
mmol/L (treatment can be interrupt up to 21 days) 
• 
Restart at same dose level maintaining appropriate 
antidiabetic treatment (eg addition of/higher dose of 
oral metformin) 
• 
Consider consult with the diabetologist  
Grade 3  
Insulin therapy initiated; 
hospitalization indicated 
Hold capivasertib up to 21 days, until resolution of 
symptoms.Consult with diabetologist. 
• 
If fasting blood glucose decreases to ≤ 160 mg/dL or ≤ 
8.9 mmol/L within 21 days and under appropriate anti-
diabetic treatment, resume capivasertib at 1 lower dose 
level. 
• 
If fasting blood glucose does not decrease to ≤ 160 
mg/dL or ≤ 8.9 mmol/L within 21 days following 
appropriate antidiabetic treatment, permanently 
discontinue capivasertib 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
Appropriate clinical management of hyperglycemia per local 
guidelines. 
• 
Consider consult with the diabetologist. 
• 
Consider permanent cessation of capivasertib 
* Participants may receive education on lifestyle changes (eg, a diabetic diet) and consider beginning 
home glucose monitoring (eg, fasting self-blood glucose monitoring [SBGM] once-daily) at the discretion 
of the investigator.  If glucose home monitoring is instituted, the capivasertib treatment decision should 
be based on the morning fasting glucose value obtained prior to the dose of capivasertib  
 
6.3.4.3 
Use of metformin 
 
Metformin is currently the preferred oral antidiabetic recommended for the management of 
hyperglycaemia occurring in patients participating in studies of capivasertib. Investigators 
should exercise caution in the dosing and management of patients receiving the 
metformin/capivasertib combination and must be vigilant for signs of renal impairment and 
metformin toxicity, such as lactic acidosis and hypoglycaemia, namely: lethargy, hypotension, 
poor urine output, drowsiness, irritation, tachypnoea, sweating, diarrhoea, and vomiting. 
 
Due to the potential interaction of metformin and capivasertib (caused by inhibition of renal 
transporters [e.g., OCT2] involved in the excretion of metformin), when taking both capivasertib 

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and metformin concurrently, patients have renal function monitored once per cycle and as 
needed if changes in health status occur (e.g., severe infection). 
 
Metformin should only be given on the days when capivasertib is also administered (the half-life 
of capivasertib is approximately 7-15 hours), and should be withdrawn when treatment with 
capivasertib is withdrawn, unless otherwise clinically indicated. 
 
Consider withholding of metformin on the days patients are due to have imaging with contrast 
(in order to reduce the already low risk of lactic acidosis) as per local guidelines. 
 
6.3.4.4 
Maculo-papular rash 
 
Dose modifications for capivasertib-related maculo-papular rash, which is the most frequent skin 
toxicity observed in patients treated with capivasertib, are provided in Table 13.  However, 
these management guidelines can be used for other skin toxicities at the discretion of the 
investigator and/or following consultation with the dermatologist. 
 
Table 13. Dose modifications for capivasertib-related maculo-papular rash  
NCI CTCAE v5 Toxicity Grade 
Management 
Grade 1 or 2 
Continue dosing at current dose and initiate 
dermatological treatment: 
• 
Topical steroid of moderate strength (twice daily) 
• 
Non-sedating oral antihistamines  
Grade ≥3 
Withhold dosing for up to 28 days and initiate 
dermatological treatment (topical steroid of moderate 
strength and non-sedating oral antihistamines) with oral 
steroid for a short course (e.g., up to 2 weeks). 
Consultation with dermatologist is advised  
• 
Improves to Grade ≤ 1 and 
tolerable within 28 days 
from onset 
• 
Continue dermatological treatment* and restart 
dosing at same dose 
• 
Improves to Grade 2 and 
tolerable within 28 days 
from onset 
• 
Continue dermatological treatment* and restart 
dosing at reduced dose (1 dose level; Table 10) 
• 
Does not improve to Grade 
2 and tolerable within 28 
days from onset 
• 
Continue dermatological treatment* and discontinue 
drug 
Recurrence of Grade ≥3 or 
Grade 4 (e.g., severe bullous, 
blistering or exfoliating skin 
conditions), or any % BSA 
associated with extensive 
superinfection, with IV 
antibiotics indicated; life-
threatening consequences) 
Discontinue capivasertib 
* In participants with persistent rash or previous occurrence of grade 3 consider secondary prophylaxis 
by continuing topical steroids and/or non-sedating oral antihistamines 
 
6.3.4.5 
Hypersensitivity 
 

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In the case of hypersensitivity reactions, capivasertib should be discontinued and 
symptomatic/supportive therapy should be initiated (including with antihistamines and/or 
steroids) as considered appropriate by the investigator/treating physician.  Drug rechallenge is 
not recommended; any subsequent consideration on rechallenge with capivasertib at the same 
or a lower dose, with its potential for recurrence of such or more severe events should be 
carefully considered against the potential benefits to the individual patient from continuation of 
capivasertib therapy.  Further management should follow local guidelines on management of 
hypersensitivity reactions. 
 
6.3.4.6 
Diarrhea  
 
Participants should be instructed to promptly contact investigators if they develop diarrhea. 
Alternative etiologies should be ruled out prior to initiating the dose modifications.  
Investigators are recommended to prescribe anti-diarrheal treatment at the first visit so that 
participants can start treatment at the first sign of diarrhea, should it occur.  Loperamide is the 
preferred anti-diarrhea agent for the management of diarrhea occurring in patients participating 
in studies of capivasertib.   
 
If diarrhea is reported, additional details regarding this AE should be collected in the appropriate 
eCRF.  Guidelines for dose modifications for capivasertib-related diarrhea are shown in Table 
14. 
 
Table 14. Dose modifications for capivasertib-related diarrhea  
NCI CTCAE v5 Toxicity Grade 
Management 
Grade 1 
Maintain same capivasertib dose. Anti-diarrheal treatment 
(e.g., loperamide) should be initiated at first report of 
diarrhoea. Maximize the supportive care (e.g. dietary 
modifications, appropriate hydration therapy and electrolyte 
supplements as clinically indicated). 
Grade 2 
Interrupt capivasertib dose (up to 21 days) until recovery to 
≤ Grade 1 and resume dosing at same dose level. Anti-
diarrheal treatment (eg loperamide) should be initiated at 
first report of diarrhoea. Maximize the supportive care (e.g. 
dietary modifications, appropriate hydration therapy and 
electrolyte supplements as clinically indicated)  
Consider secondary prophylaxis* 
Grade ≥3 
 
Interrupt capivasertib dose (up to 21 days) and institute 
appropriate anti-diarrheal treatment  
• 
Improves to Grade ≤1 within 
21 days 
 
Resume dosing at same dose or one reduced dose level 
(Table 10) as clinically appropriate maintaining treatment 
for toxicity as necessary and/or start secondary 
phophylaxis* 
• 
Does not improve to Grade 
≤1 after 21 days or remains 
clinically intolerable 
Discontinue drug  

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Table 14. Dose modifications for capivasertib-related diarrhea  
NCI CTCAE v5 Toxicity Grade 
Management 
Recurrence of Grade ≥2 or 
clinically significant or 
intolerable toxicity despite 
secondary prophylaxis 
Interrupt capivasertib dose (up to 21 days), maintaining 
appropriate anti-diarrhoeal treatment 
Improves to Grade ≤1 or 
becomes clinically tolerable 
within 21 days  
 
Resume dosing up to two reduced dose levels as clinically 
appropriate maintaining treatment for toxicity as necessary 
and/or maintaining secondary phophylaxis* 
 
Does not improve to Grade ≤1 
clinically significant or remains 
clinically intolerable after 21 
days 
Discontinue capivasertib 
*In participants with persistent Grade 1 diarrhea (e.g., loperamide 2 mg, 2 to 4 times daily). 
 
6.3.5 MANAGEMENT OF SELUMETINIB-RELATED TOXICITIES 
 
Any selumetinib-related toxicity observed during the course of the study can be managed by 
interuption of the dose of study treatment or dose reductions according to the dose reductions 
provided in Table 15 and Table 16, and the toxicity management guidelines provided in 
Sections 6.3.5.1 to 6.3.5.8. Unless otherwise stated, two dose reductions are allowable after 
which study treatment should be discontinued. 
 
Table 15. Selumetinib recommended dosage based on body surface area 
Body Surface Area (BSA) 
Recommended Dosage 
0.55 – 0.69 m2 
20 mg in the morning and 10 mg in the evening  
0.7 – 0.89 m2 
20 mg twice daily 
0.90 – 1.09 m2 
25 mg twice daily 
1.10 – 1.29 m2 
30 mg twice daily 
1.30 – 1.49 m2 
35 mg twice daily 
1.50 – 1.69 m2 
40 mg twice daily 
1.70 – 1.89 m2 
45 mg twice daily 
≥1.90 m2 
50 mg twice daily 
a. 
The recommended dosage for participants with a BSA <0.55 m2 has not been established 
 
Treatment with selumetinib should be temporarily interrupted if one of the following AEs occurs 
and is considered related to treatment with selumetinib: 
• 
Any intolerable AE regardless of grade. 
• 
Any AE CTCAE grade 3. 
 
On improvement of the AE to CTCAE grade 1 or less within 4 weeks of onset, study treatment 
may be restarted at the discretion of the investigator.  If restarted, it must be at a reduced dose 
as shown in Table 16. If the AE does not resolve to CTCAE Grade 1 or less within 4 weeks of 
onset, study intervention must be permanently terminated unless otherwise specified. 
  
The dose modification procedure is shown in Table 16.  Two step dose modification is applied 

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in the study. Any participants with 2 prior dose reductions who experience a toxicity that would 
cause a third dose reduction must be discontinued from study intervention.  Dose must not be 
re-escalated following dose reduction apart from to account for increase due to BSA, in 
accordance with Table 16.  For example, if a participant has a BSA of 1.8 m2 and starts on a 
dose of 45 mg BID and then has a dose reduction to 35 mg AM, 30 mg PM then a subsequent 
BSA increase to 1.9 m2 would mean the participant should be dose adjusted to 35 mg BID. 
 
Note that if selumetinib treatment is interrupted for > 4 weeks for any reason other than AEs 
related to selumetinib eg, investigations, unplanned procedures and AEs unrelated to 
selumetinib, re-start of treatment must be discussed with the Investigator. 
 
Treatment with selumetinib should be permanently discontinued for any CTCAE Grade 4 toxicity 
that is at least partially related to selumetinib.  However, if it is felt to be in the best interest of 
the participant, interruption of selumetinib with potential to restart at a reduced dose upon 
resolution to Grade 1 or less may be considered on a case-by-case basis for CTCAE Grade 4 
AEs in consultation with the Principal Investigator. 
 
Table 16. Selumetinib recommended dose reduction for adverse reactions 
BSA 
Initial Selumetinib Dosea 
(mg/twice daily) 
First dose reduction 
(mg/dose) 
Second dose reduction 
(mg/dose)b 
Morning 
(AM) 
Evening 
(PM) 
Morning 
(AM) 
Evening 
(AM) 
0.55 – 0.69 m2 
20 mg in the morning and 
10 mg in the evening 
10 
10 
10 once daily 
0.7 – 0.89 m2 
20 
20 
10 
10 
10 
0.90 – 1.09 m2 
25 
25 
10 
10 
10 
1.10 – 1.29 m2 
30 
25 
20 
20 
10 
1.30 – 1.49 m2 
35 
25 
25 
25 
10 
1.50 – 1.69 m2 
40 
30 
30 
25 
20 
1.70 – 1.89 m2 
45 
35 
30 
25 
20 
≥1.90 m2 
50 
35 
35 
25 
25 
a. Based on BSA as shown in Table 15 
b. Permanently discontinue selumetinib in participants unable to tolerate selumetinib after two (2) dose 
reductions.  
 
6.3.5.1 
Diarrhea 
 
Participants should be instructed to promptly contact investigators if they develop diarrhea. 
Investigators are recommended to prescribe anti-diarrheal treatment at the first visit so that 
participants can start treatment at the first sign of diarrhea, should it occur.  Alternative 
etiologies should be ruled out prior to initiating the dose modifications.  If diarrhea is reported, 
additional details regarding this AE should be collected in the appropriate eCRF.  Guidelines for 
dose modifications for selumetinib-related diarrhea are shown in Table 17.  
 

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Table 17. Selumetinib Recommended Management for Diarrhea 
Grade 1 or 2 uncomplicated diarrhea 
Continue selumetinib treatment and monitor as clinical indicated. Treat with loperamide in 
accordance to local practice. Dietary management* 
 
(1) If diarrhea resolving or resolved after 12 hours of loperamide, then: 
• 
Continue loperamide for 12 hours after diarrhoea resolved  
• 
Adjust diet 
(2) If persistent diarrhea not resolved after 12 hours of loperamide and remains 
uncomplicated CTC Grade 1 or 2: 
• 
Consider increasing loperamide to maximum dose & frequency in accordance to local 
labels.  
• 
Consider additional agents according to local practice if loperamide is not adequate to 
control diarrhea as a single agent 
o If diarrhea resolves or resolved after 24 hours, then continue loperamide for 12 
hours after diarrhoea resolved and adjust diet 
o If persistent diarrhea not resolved after 24 hours, then  
 
Interrupt selumetinib dose,  
 
Conduct full examination,  
 
Treat according to local practice (e.g., rehydration, electrolytes, 
antibiotics, hospitalization) 
Grade 1 or 2 Complicated** Diarrhea or Grade 3 or 4 Diarrhea at any time 
• 
Interrupt selumetinib dose, 
• 
Hospitalization. 
• 
Treat according to local practice (eg. rehydration, electrolytes, antibiotics). 
*BRAT diet (bananas, rice, apple sauce, toast, plain pasta), readily digestible food, avoidance of 
lactose-containing products and fried, fatty or spicy foods, increased fluid intake (8-10 glasses of clear 
fluids/day (including water, clear broth, fluids containing salt and sugar). 
**Diarrhea complicated by associated vomiting or inability to take oral fluids; marked abdominal 
distension or cramping; bloody stools, fever or symptoms of hypotension 
 
6.3.5.2 
Visual Disturbances 
 
Participants experiencing visual disturbances should undergo a complete ophthalmologic 
examination (to evaluate for selumetinib-related toxicity such as retinal layer separation/edema), 
as described in Section 7.1.9. Consider interruption of selumetinib at investigator discretion 
whilst awaiting ophthalmologic assessment. Refer to Table 18 for further management 
guidelines.  
 
Table 18. Selumetinib Management of Retinal Pigment Epithelial Detachment (RPED), 
Central Serous Retinopathy (CSR), or Retinal Vein Occlusion (RVO) 
No diagnosis of RPED/CSR/RVO: 
• 
Continue selumetinib 
• 
Manage visual symptoms according to local practice 

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Table 18. Selumetinib Management of Retinal Pigment Epithelial Detachment (RPED), 
Central Serous Retinopathy (CSR), or Retinal Vein Occlusion (RVO) 
Diagnosis of RPED / CSR: 
(1) If best corrected visual acuity 20/40 or better, or not worsened from baseline if there is 
pre-existing visual impairment, then: 
• 
Continue selumetinib 
• 
Repeat ophthalmic assessments every 3 weeks until resolution 
(2) If best corrected visual acuity worse than 20/40, or worsened from baseline if there is pre-
existing visual impairment, then: 
• 
Interrupt selumetinib 
• 
On resolution to 20/40 or better, or baseline if there is pre-existing visual impairment, 
within 3 weeks, selumetinib may be restarted after a dose reduction 
Diagnosis of retinal vein occlusion (RVO) 
• 
Discontinue selumetinib 
 
6.3.5.3 
Rash 
 
Treatment of rash should be managed in accordance with institutional standards. Table 19 
provides additional management guidelines.  To reduce rashes, prophylactic recommendations 
are to start on day 1 of treatment with selumetinib and continue for the whole duration of 
treatment. This may include applying a skin moisturiser (thick, alcohol-free) at bedtime, avoiding 
excessive exposure to sunlight, and avoiding the use of topical retinoids or benzoyl peroxide, as 
these are not recommended. 
 
Table 19. Selumetinib Management of Rash 
Toxicity 
Dose Guidelines 
Recommended Management 
Grade 1 or 2 
Tolerable Rash 
• 
Continue Selumetinib 
treatment and monitor as 
clinical indicated. 
• 
Manage rash as per 
paediatric or adult 
treatment 
recommendations. 
Grade 1 rash: 
• 
Apply a mild/moderate strength 
• 
topical steroid 
• 
and/or topical antibiotic. 
 
Grade 2 rash (tolerable): 
• 
Apply a moderate strength topical 
steroid and consider an oral 
antibiotic 
Grade 2 Intolerable, 
or  
Grade ≥3 
• 
Consider Selumetinib 
dose interruption. 
• 
Consider referral to a 
dermatologist. 
• 
Manage rash as per 
paediatric or adult 
treatment 
recommendations. 
 
If rash has improved to 
Grade 2 tolerable or less 
within 4 weeks, restart 
selumetinib at original dose 
Grade ≥3 rash or Grade 2 rash 
considered by the participant to be 
intolerable: 
• 
Apply moderate strength topical 
steroid and consider an oral 
antibiotic. If an infection is 
suspected, consider other broad 
spectrum antibiotic cover. 

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or consider reduced dose. 
 
6.3.5.4 
Paronychia 
 
Treatment of rash should be managed in accordance with institutional standards. Table 20 
provides additional management guidelines.   
 
Table 20. Selumetinib Management of Paronychia 
Toxicity 
Dose Guidelines 
Recommended Management 
CTC Grade 1 
or 2 Tolerable  
Continue selumetinib 
treatment and monitor 
as clinical indicated. 
 
Manage per 
treatment 
recommendations. 
Grade 1: Treat the affected area by soaking in 
vinegar solution twice daily (1 part vinegar to 2 
parts water), plus topical antibiotic mupirocin (or 
similar agent) twice daily. 
 
 
Grade 2 
Intolerable 
or 
Grade ≥3 
• 
Consider 
selumetinib dose 
interruption. 
• 
Consider referral 
to a dermatologist. 
• 
Manage 
paronychia as per 
treatment 
recommendations. 
 
If paronychia has 
improved to Grade 2 
tolerable or less 
within 4 weeks, then 
re-start selumetinib at 
original dose or 
consider reduced 
dose. 
Grade 2: Treat the affected area by soaking in 
vinegar solution twice daily (1 part vinegar to 2 
parts water), plus systemic antibiotic (e.g., keflex, 
clindamycin), as well as high potency steroid (e.g., 
0.05% clobetasol ointment covered with saran 
wrap  or flurandrenolide tape (e.g., cordran tape) 
applied at bedtime. This should be removed in the 
morning. 
 
Grade 3: If severe, seek consult for incision & 
drainage or surgical management. 
 
*If granulation tissue present, consider use of silver 
nitrate under supervision 
 
For participants who do not undergo drainage, silver nitrate may be used, as well as topical 
bactroban, steroids, and/or antifungals.  Silver nitrate is only of value when there is open 
inflamed skin or granulation tissue (e.g. pyogenic-granuloma-like lesions). If the periungual skin 
is swollen but intact (whether infectious or non-infectious), silver nitrate is not recommended. 
Participants should be cautioned to avoid trauma to the area. Podiatry consult may be 
considered for partial nail removal. 
 
Participants who undergo incision and drainage and are found to have no infectious organisms 
on culture, should be treated as above. If infection is identified, participants may be treated with 
systemic antibiotics (oral tetracyclines). If paronychia recurs or develops in other fingers or toes, 
Flurandrenolide (e.g. Cordran) tape or topical steroid cream such as triamcinolone can be used 
in the morning and Bactroban and Nizoral topical ointments in the evening. 
 
6.3.5.5 
Oral Mucositis 
 

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Oral care guidelines for events of oral mucositis and dry mouth: 
• 
Participants should be encouraged to follow a daily oral health care regimes, both before 
and during treatment with selumetinib. 
• 
Participants with a healthy mouth may use non alcoholic mouthwash 4 to 6 times daily (e.g. 
after each meal), or according to the instructions, during the study. 
• 
Saline mouthwashes (Sodium chloride 0.9%) are preferred to alcohol-based mouth washes 
in cases of stomatitis, and should be used at a different time than toothbrushing (e.g. after 
tea). 
• 
Use of a mouthwash immediately after selumetinib intake is recommended. 
• 
The tongue can be gently brushed (if not sore) with a soft toothbrush. 
• 
Participants with, or at risk of, stomatitis should not use commercial/over-the-counter 
mouthwashes because of the alcohol content and astringency. Chlorhexidine mouthwashes 
are not recommended for the treatment of established stomatitis. 
• 
The mouth should be regularly inspected by the participants and healthcare professionals. 
• 
Teeth should be brushed twice daily with a fluoride toothpaste and soft toothbrush, in the 
morning before breakfast and last thing in the evening before bed, about 30 minutes after 
eating. The toothbrush should be replaced regularly (at least every 3 months). 
• 
Participants with stomatitis should change their toothbrush every 4 - 6 weeks. 
• 
Investigators or treating physician should consider culture to rule out herpes simplex. 
• 
Investigators or treating physician should consider treating stomatitis at an early stage (i.e., 
CTCAE grade 1) or as soon as the participant complains of a sore mouth. Consider using an 
oral topical analgesic, with or without topical steroids, depending on the patient’s clinical 
condition and institutional standards. 
 
6.3.5.6 
Creatine Kinase (CK) Elevation 
 
Elevated CK should be managed in accordance with institutional standards. Table 21 provides 
additional management guidelines.   
 
Table 21. Selumetinib Management of Elevated Creatine Kinase 
Toxicity 
Management 
Grade 1 or 2, 
CK > ULN to ≤ 5x ULN  
Continue selumetinib and CK monitoring as per protocol or more 
frequently if onset of new or worsening muscle symptoms or as per 
Investigator’s clinical judgment 
Grade 3,  
CK > 5x to ≤10x ULN 
• 
Consider selumetinib interruption 
• 
Evaluate patient for new or worsening of existing muscle 
symptoms 
(1) If no muscle symptoms, then: 
• 
Continue selumetinib and CK monitoring as per protocol or 
more frequently if onset of new or worsening muscle 
symptoms or as per Investigator’s clinical judgment 
(2) If new or worsening muscle symptoms, then: 
• 
Interrupt selumetinib 
o Measure serum creatinine and urine myoglobin levels 
o Consider muscle biopsy or electromyography 
• 
If no evidence of rhabdomyolysis, then: 
o If CK levels have improved to grade 1 or less and 
symptoms resolve to baseline within 3 weeks, 
selumetinib may be restarted at reduced dose 

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Table 21. Selumetinib Management of Elevated Creatine Kinase 
Toxicity 
Management 
• 
If evidence of rhabdomyolysis, then: 
o Discontinue selumetinib 
o Manage according to local institutional standards 
Grade 4 
CK > 10 x ULN  
• 
Interrupt selumetinib 
o Measure serum creatinine and urine myoglobin levels 
o Consider muscle biopsy or electromyography 
• 
If no evidence of rhabdomyolysis, then: 
o If CK levels have improved to grade 1 or less and 
symptoms resolve to baseline within 3 weeks, selumetinib 
may be restarted at reduced dose 
• 
If evidence of rhabdomyolysis, then: 
o Discontinue selumetinib 
o Manage according to local institutional standards 
 
6.3.5.7 
Dyspnea 
 
The following should be considered for investigation of new or worsening of pre-existing 
dyspnea, and may include: based on clinical examination: chest X-ray: P-A and lateral view, 
echocardiography, ECG; WBC, Hb, BNP, troponin, sputum culture, renal panel, blood or urine 
culture. Consider at the investigator discretion, interruption of selumetinib whilst investigations 
are ongoing.  Table 22 provides guidelines for the investigation and management of dyspnea 
that may be related to selumetinib.  
 
Table 22. Selumetinib Management of Dyspnea 
If diagnosis other than pneumonitis/ILD, then: 
• 
Manage according to local institutional standards 
(1) If dypnea resolves to baseline, then continue selumetinib: 
(2) If treatment is ineffective, then: 
• 
Perform high resolution CT scan.  
• 
Consider respiratory consultation. 
• 
If no diagnosis of pneumonitis/ILD by high resolution CT, and dyspnea not resolved to 
baseline, then: 
o Cardiology / respiratory consultation. 
If suspected pneumonitis/ILD or no obvious cause of dyspnea, then: 
• 
Perform high resolution CT scan.  
• 
Consider respiratory consultation. 
(1) If no diagnosis of pneumonitis/ILD by high resolution CT, and dyspnea not resolved to 
baseline, then: 
• 
Cardiology / respiratory consultation. 
(2) If diagnosis of pneumonitis/ILD by high resolution CT, then: 
• 
Treat according to local practice. Selumetinib will be held for grade ≥2 pneumonitis for 
up to 3 weeks. 
• 
If event resolves to Grade ≤1 after withholding for up to 3 weeks then selumetinib may 
be restarted. Consider reduced dose. 
• 
If event does not resolve to Grade ≤1 by 3 weeks then discontinue selumetinib. 
 

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6.3.5.8 
Left Ventricular Ejection Fraction (LVEF) Reduction or Dysfunction 
 
Refer to Table 23 for selumetinib management of LVEF reduction or dysfunction.  
 
Table 23. Selumetinib Management of LVEF 
Toxicity 
Management  
LVEF ≥ LLN 
If LVEF has decreased from baseline ≥10 percentage points, then: 
• 
Continue selumetinib.  
• 
ECHO after 3-6 weeks. 
LVEF < LLN, 
but >39% 
(1) If LVEF has decreased from baseline <10 percentage points, then: 
• 
Continue selumetinib. 
• 
Cardiology consult 
• 
ECHO after 3-6 weeks. 
 
(2) If LVEF has decreased from baseline ≥10 percentage points but <20 
percentage points, then: 
• 
Hold selumetinib.  
• 
Cardiology consult. 
• 
ECHO after 3-6 weeks. 
• 
If LVEF recovers to ≥ LLN within a period of 3 months or less, 
selumetinib may be restarted at a reduced dose based on cardiology 
recommendation. 
 
(3) If LVEF has decreased from baseline ≥20 percentage points, then: 
• 
Discontinue selumetinib.  
• 
Manage according to local practice. 
• 
Refer to a cardiologist. 
LVEF < 39%, 
or  
Grade ≥3 Left 
Ventricular 
Systolic 
Dysfunction  
• 
Discontinue selumetinib. 
• 
Manage according to local practice. 
• 
Refer to a cardiologist. 
 
6.3.6 MANAGEMENT OF CERALASERTIB-RELATED TOXICITIES 
 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions.  Repeat dose interruptions are allowed as required, 
for a maximum of 3-4 weeks on each occasion (depending on the toxicity and treatment arm).  If 
study treatment cannot be restarted within the specified period, then the participant must 
permanently discontinue study treatment.   
 
If a participant experiences a clinically significant and/or unacceptable toxicity, dosing will be 
interrupted, and supportive therapy administered as required. If the toxicity resolves or reverts to 
≤ CTCAEv5 grade 1 or 2 (depending on the toxicity, seeTable 24) treatment with ceralasertib 
may be restarted using the rules in Table 24 and Table 25 for dose modifications. Participants 
who are at the lowest possible dose, or who have their dose previously reduced to the lowest 
possible dose and who have demonstrated an acceptable response to the dose interruption 
may be permitted to restart at the lowest dose level at the discretion of the Investigator.  

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If the toxicity does not resolve to ≤ CTCAEv5 grade 1 or 2 (depending on the toxicity) or the 
patient is not showing clinical benefit, then the patient should be discontinued from treatment 
and observed until resolution of the toxicity. 
 
Repeat dose interruptions are allowed as required for a maximum of 28 days on each occasion 
as recommended in Table 4. If the duration of ceralasertib dose interruption is longer than 28 
days, the case should be discussed with the Study Physician. 
  
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a patient cannot restart study treatment within 28 days for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the Study Physician.  
 
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is 
required for any biopsy procedure. 
 
The dose of study treatment must not be adjusted under any other circumstances unless prior 
agreement is given by the study physician. 
 
All dose modifications and interruptions (including any missed doses) and the reasons for the 
modifications/interruptions must be recorded. 
 
6.3.6.1 
Dose reductions for Ceralasertib monotherapy 
 
Refer to Table 24 and Table 25 for dose modification and stopping criteria for ceralasertib.  
 
Please note that for simultaneous toxicities (for example, anaemia and neutropenia), the event 
should be considered singular and no further dose modification should be made providing that 
both toxicities resolve within 28 days. However, sequential toxicities (for example, anaemia 
followed by neutropenia) should follow the guidance below; if a recent dose reduction has been 
made, a second modification may be required before beginning the next cycle.  
 
Once dose is reduced, escalation is not permitted. 
 
 Table 24. Guidance for dose modifications and interruptions for ceralasertib 
Event  
Action  
Grade 1 neutropenia and/or  
thrombocytopenia 
Ceralasertib dosing may continue if neutrophil 
count is ≥1500/mm3 and/or platelet count is 
≥75,000/mm3.  
Grade 1-2 toxicities (except 
neutropenia and 
thrombocytopenia) 
Investigator decision whether to interrupt 
ceralasertib (max 28 days) or continue treatment. 
Treatment may be resumed at the same dose 
level or with a dose reduction by 1 level.  
Grade 2 neutropenia or  
grade 3 anaemia 
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment e.g. transfusion, 
until AE improves to at least neutrophil count 
≥1500/mm3 and haemoglobin ≥8.0 g/dL, then 

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restart reducing the dose of ceralasertib by 1 
levela. 
 
If a further dose reduction is required after the 
level 3 dose reduction, the patient must stop 
treatment. 
Grade 2-3 thrombocytopenia 
 
First occurrence 
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment until platelets 
improve to at least ≥100,000/mm3. At resolution, it 
is not mandatory to lower the dose as blood 
counts may recover during the “off period” on the 
intermittent schedule. If blood counts do not 
recover by the start of the next dosing period, 
ceralasertib should be restarted with a dose 
reduction by 1 level for ceralasertib. 
Subsequent occurrences 
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment. Treatment may 
be restarted with a reduced dose of ceralasertib 
when the toxicity is resolved or investigator 
discretion to stop treatment. 
 
Grade 4 thrombocytopenia 
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment; investigator 
discretion on whether to restart treatment with a 
dose reduction by 1 dose level ceralasertib when 
the platelet count has recovered to ≥100,000/mm3 
or stop treatment. 
Grade 3-4 toxicity (except 
grade 3 anaemia and grade 3-
4 thrombocytopenia) 
First occurrence 
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment; restart 
treatment with a dose reduction by 1 level for 
ceralasertib when the toxicity is resolved (grade 1 
or 2 depending on the toxicity or returns to 
baseline). 
 
Subsequent occurrences  
Investigator discretion on whether to interrupt 
ceralasertib (max 28 days) or to stop treatment. 
Restart treatment reduced by 1 or 2 levels dose of 
ceralasertib.  
 
If a further dose reduction is required after the 
level 3 dose reduction, the patient must stop 
treatment. 

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Table 25. Dose reduction levels for ceralasertib  
Initial dose 
240 mg BID days 1–14 
Level 1 dose reduction 
160 mg BID days 1–14 
Level 2 dose reduction 
120 mg BID days 1–14 
Level 3 dose reduction 
80 mg BID days 1–14 
Level 4 dose reduction 
Stop treatment 
 
6.3.6.2 
Individual stopping criteria 
 
6.3.6.2.1. Hepatic 
 
• ALT or AST or ALP* > 5 x ULN 
• ALT or AST or ALP* > 3 x ULN with the appearance of symptoms associated with a clinical 
diagnosis of hepatitis including right upper quadrant pain or tenderness, fever, rash or 
eosinophilia (>5%) 
• [ALT or AST > 3 x ULN] and [total bilirubin > 2 x ULN or INR† > 1.5 or other evidence of 
impairment to the synthesis function of the liver] 
* In the presence of bone mets assess bone specific isoform of raised ALP in the presence of a 
raised gamma-GT (to ensure the ALP change is specific to the liver) 
† Unless patient is receiving warfarin 
Please refer to Appendix G. 
 
6.3.6.2.2. Cardiovascular 
• Clinically significant hypotension defined as an asymptomatic decrease of more than 20 
mmHg in systolic blood pressure to below 70 mmHg persisting for at least 10 minutes. 
• Symptomatic orthostatic fall in systolic blood pressure of more than 20 mmHg compared to 
resting supine systolic blood pressure. 
 
6.3.6.3 
Ceralasertib as CYP3A drug substrate 
 
The principal enzyme for metabolizing ceralasertib is CYP3A4.  If there is no suitable alternative 
concomitant medication other than a potent inhibitor of CYP3A, the investigator must interrupt 
ceralasertib for the duration of the potent CYP3A inhibitor and wait for the required wash-out 
period (five half-lives) before dosing ceralasertib again.  If potent CYP3A inducers are 
considered necessary for the participant’s safety and welfare, this may diminish the clinical 
efficacy of ceralasertib, and the participant should be monitored carefully for any change in the 
Vomiting  
If vomiting occurs shortly after ceralasertib is 
swallowed, the dose should only be replaced if all 
of the intact tablets can be counted. Resume with 
the following scheduled dose. 
Missed dose  
Allowed to take the scheduled dose up to 2 hours 
after the scheduled dose time. If greater than 2 
hours, the missed dose should not be taken, and 
patient should continue with next dose at allotted 
time.  
a This table is for guidance. Therefore, for example, it may be deemed appropriate by 
the investigator to reduce the dose by more than one dose level depending on the 
individual patient circumstances. 

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efficacy of the study treatment.  Refer to Section 6.6.5 for additional information. 
 
6.3.6.4 
Ceralasertib as Pgp drug substrate 
 
Ceralasertib is a Pgp substrate. Co-administration of Pgp inhibitors or inducers may affect 
exposure to ceralasertib and, therefore, should not be co-administered with ceralasertib. If the 
use of any inhibitors or inducers of Pgp are considered necessary for the participant’s safety 
and welfare, the investigator must interrupt ceralasertib for the duration of the Pgp inhibitor or 
inducer and wait for the required wash-out period of the Pgp modulator (five half-lives) before 
dosing ceralasertib again.  Refer to Section 6.6.5 for additional information. 
 
6.3.6.5 
Ceralasertib as Pgp drug substrate 
 
Ceralasertib is also a substrate of BCRP. Co-administration of BCRP inhibitors or inducers may 
affect exposure to ceralasertib; therefore, it is recommended that the investigators must 
interrupt ceralasertib for the duration of the BCRP inhibitor or inducer and wait for the required 
wash-out period of the BRCP modulator (five half-lives) before dosing ceralasertib again. Refer 
to Section 6.6.5 for additional information. 
 
 
TREATMENT PERIOD AND MAINTENANCE 
 
A treatment cycle is defined as the first day of study drug administration (Day 1) through and 
including Day 28.  All eligible participants will receive cycle 1 induction treatment with 4 weeks 
of olaparib (28 days ± 7 days), as described in Section 6.1.1.  After completing the 4-week 
Cycle 1 olaparib monotherapy, eligible participants will proceed to receive olaparib in 
combination with either durvalumab, selumetinib, or capivasertib, or ceralasertib monotherapy, 
based on treatment arm assignment for 12 cycles (i.e., approximately 48 weeks).  Following the 
completion of all 13 on-study treatment cycles (for all study arms), participants will be 
considered off-treatment.  Participants deriving clinical benefit from treatment may, at the 
investigator's discretion and in the absence of disease progression or unacceptable toxicity, 
continue on assigned therapy beyond the planned 13 cycles.  Clinical data regarding survival 
outcomes for all participants will continue to be collected for the duration of the trial (i.e., up to 
12 months post-treatment). 
 
 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases, and 
supportive care agents, such as pain medications, anti-emetics, and antidiarrheals are allowed 
in general. The participant must be told to notify the investigational site about any new 
medications begun after the start of the study treatment. All medications (other than 
investigational products) and significant non-drug therapies (including vitamins, herbal 
medications, physical therapy, and blood transfusions) administered during the study must be 
listed on the appropriate eCRF.  
 
6.5.1 PNEUMONITIS 
 
Grade 2 events may be treated with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 
Participants with Grade 3-4 events should be immediately treated with intravenous steroids. 
Additional anti-inflammatory measures may be administered as needed. Prophylactic antibiotics 

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for opportunistic infections in the case of prolonged steroid administration may also be given. If 
the participant is determined to have study drug-associated pneumonitis, the suggested 
treatment plan is detailed in the separately provided durvalumab TMG. 
 
6.5.2 DIARRHEA/COLITIS 
 
From screening onwards, should a participant develop diarrhea, then these symptoms should 
be reported as AEs (see Section 9.2) and appropriate treatment of the event given. 
 
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and bowel perforation 
(such as peritoneal signs and ileus). In symptomatic participants, infectious etiologies should be 
ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should be 
considered.  
 
For Durvalumab: In participants with severe enterocolitis, durvalumab will be permanently 
discontinued, and treatment with systemic corticosteroids should be initiated at a dose of 1 to 2 
mg/kg/day of prednisone or equivalent. When symptoms improve to grade 1 or less, 
corticosteroid taper should be started and continued over at least 1 month.  
 
In participants with moderate enterocolitis, durvalumab should be withheld, and antidiarrheal 
treatment should be started. If symptoms are persistent for more than one week, systemic 
corticosteroids should be initiated (e.g., 1 to 2 mg/kg/day of prednisone or equivalent). 
 
All participants that experience diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. 
 
6.5.3 NAUSEA/VOMITING 
 
From screening onwards, should a participant develop nausea or vomiting, then these 
symptoms should be reported as AEs (see Section 9) and appropriate treatment of the event 
given. 
 
For Olaparib: No routine prophylactic anti-emetic treatment is required at the start of treatment; 
however, the participant should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter per institutional guidelines.  Alternatively, olaparib 
tablets can be taken with a light meal/snack. 
 
For Durvalumab: nausea and vomiting should be treated aggressively, and consideration should 
be given in subsequent cycles to the administration of prophylactic antiemetic therapy according 
to standard institutional practice. Participants should be strongly encouraged to maintain liberal 
oral fluid intake.  
 
6.5.4 ANEMIA 
 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the treatment of 
anemia but should be clearly noted as concurrent medications 
 
For Olaparib or Ceralasertib: Common treatable causes of anemia (e.g., iron, vitamin B12 or 
folate deficiencies and hypothyroidism) should be investigated and appropriately managed per 

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institutional guidelines.  In some cases, the management of anemia may require blood 
transfusions.  For cases where participants develop prolonged hematological toxicity (≥2 week 
interruption/delay in program treatment due to CTCAE grade 3 or worse anemia and/or 
development of blood transfusion dependence), refer to Sections 6.3.1.3 (olaparib) and 6.3.6 
(ceralasertib) for the management of prolonged hematological toxicity. 
 
6.5.5 THROMBOCYTOPENIA 
 
Transfusion of platelets may be used if clinically indicated. Idiopathic thrombocytopenic purpura 
should be ruled out before initiation of platelet transfusion. 
 
6.5.6 DIABETES MELLITUS 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria.  
 
For Capivasertib: hyperglycemia should be managed as described in Section 6.3.4.2.  
 
6.5.7 HYPOPHYSITIS / ADRENAL INSUFFICIENCY 
 
Participants showing Grade 2 symptoms may be treated with corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered. 
Participants with Grade 3-4 events should be treated with an initial dose of IV corticosteroids, 
followed by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
6.5.8 HYPERTHYROIDISM OR HYPOTHYROIDISM 
 
Thyroid disorders can occur at any time during treatment. Participants should be monitored for 
changes in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
Participants with grade 2 hyperthyroidism events may receive non-selective beta-blockers (e.g., 
propranolol) as a suggested initial therapy. Participants with grade 2 hypothyroidism, may 
receive thyroid hormone replacement therapy, with levothyroxine or liothyronine, per institutional 
guidelines.  
 
Participants with Grade 3-4 hyperthyroidism may be treated with an initial dose of IV 
corticosteroid followed by oral corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
6.5.9 HYPERPHOSPHATEMIA 
 
Management of hyperphosphatemia, including diet modifications, phosphate binders, and 
diuretics, should be in accordance with institutional guidelines. 
 
6.5.10 HEPATIC ADVERSE EVENTS 
 

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Participants with Grade 2 events should be treated with IV or oral corticosteroids per institutional 
guidelines. Participants should undergo more frequent monitoring (i.e., weekly) of liver function 
until values return to baseline. 
  
Participants with Grade 3-4 events should be treated with IV corticosteroids for 24 to 48 hrs. 
Once symptoms resolve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks. 
 
6.5.11 NEPHRITIS AND RENAL FAILURE 
 
Participants with Grade 2 events may be treated with corticosteroids. For those with Grade 3-4 
events, treat with systemic corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
 
6.5.12 INFECTION PROPHYLAXIS 
 
Participants with documented infectious complications should receive oral or IV antibiotics or 
other anti-infective agents as considered appropriate by the Investigator for a given infectious 
condition, according to standard institutional practice.   
 
6.5.13 IMMUNE-RELATED AND/OR HYPERSENSITIVITY REACTIONS 
 
In the event of suspected immune-related adverse events (irAEs) or hypersensitivity, the 
durvalumab infusion or other study agents (e.g., selumetinib) should be immediately 
discontinued, and appropriate supportive therapy should be administered per institutional 
guidelines, which may include (but not limited to): epinephrine, IV fluids, corticosteroids, 
vasopressors, oxygen, bronchodilators, antihistamines, or acetaminophen.  
 
Participants with Grade 2 symptoms may be premedicated with Diphenhydramine, 50 mg PO (or 
equivalent dose of antihistamine), as well as acetaminophen, 500-1000 mg PO (or equivalent 
dose of antipyretic). 
 
Durvalumab should be withheld in participants with Grade 3 and Grade 4 irAEs. Systemic 
corticosteroids are indicated in addition to appropriate symptomatic treatment. Prednisone or 
equivalent may be utilized at 1 to 2 mg/kg per day. Steroid taper should be considered once 
symptoms improve to Grade 1 or less and tapered over at least 4 weeks. Durvalumab should be 
discontinued if unable to reduce corticosteroid dose to <10 mg per day prednisone or equivalent 
within 12 weeks of toxicity.  
 
Refer to Section 6.3.4.5 regarding the management of capivasertib-related hypersensitivity. 
 
6.5.14 DIET 
 
Participants should maintain a normal diet unless modifications are required to manage an AE, 
such as diarrhea, nausea, or vomiting. 
 
6.5.15 BLOOD DONATION 
 
Participants should not donate blood while participating in this study, or for at least 90 days after 
receipt of the final dose of durvalumab, or until after 4-5 times the half-life of durvalumab or until 
the time specified in the prescribing information of durvalumab, whichever occurs longest. 

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Participants assigned to receive selumetinib should avoid donating blood for at least 12 weeks 
after receiving the last dose of the study medications or for longer if required in accordance with 
the prescribing information for the concomitantly administered olaparib.   
 
6.5.16 DERMATOLOGICAL CARE  
 
Rashes (acneiform [papulopustular]) should be managed according to institutional standards.  
Early initiation of treatment is recommended for dermatological events that are known to occur 
with study agents (e.g., selumetinib).  Dry skin is commonly reported during treatment with 
selumetinib monotherapy (typically CTCAE Grade 1), and the use of alcohol-free moisturizer at 
bedtime is recommended during treatment with this study drug. 
 
Phototoxicity is not designated an important risk, but as ceralasertib is an inhibitor of DNA 
damage repair, and participants are advised to take precautions when outside in the sun, e.g., 
limiting the duration of sun exposure, wearing protective clothing (hat and sunglasses) and 
sunscreen. 
 
6.5.17 VISUAL FUNCTION 
 
Blurred vision, generally CTCAE Grade 1, has been reported in some patients enrolled in 
studies of selumetinib monotherapy or in combination with other anti-cancer agents.  AEs 
consistent with CSR/RPED and with retinal vein occlusion have also been reported in a small 
number of patients receiving treatment with selumetinib.  Ophthalmologic exams in participants 
with reported visual AEs or change in visual acuity should be performed according to 
institutional standards. Consultation with an ophthalmologist is recommended as clinically 
appropriate.  
 
6.5.18 CONTRACEPTION 
 
Study agents described within this protocol may have adverse effects on a fetus in utero.  Non-
pregnant, non-breast-feeding women may be enrolled if they are willing to use appropriate 
methods of birth control described in Appendix D) or are considered highly unlikely to conceive.  
 
Highly unlikely to conceive women are defined as:  
 
1. Surgically sterilized, or  
2. Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
a. Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
b. Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 

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3. Not heterosexually active for the duration of the study.  
 
Participants should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study, they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in Section 9.7.  If there is any question that 
a participant will not reliably comply with the requirements for contraception, they should not be 
entered into the study. 
 
6.5.19 USE IN PREGNANCY 
 
If a participant inadvertently becomes pregnant while on treatment with olaparib and/or 
durvalumab, the participant will immediately be removed from the study. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The pregnancy will be recorded on the eCRF and reported by the 
Investigator to the IRB (refer to Section 9.7.3) and any other entity, as required per protocol 
 
6.5.20 USE IN NURSING WOMEN 
 
It is unknown whether any of the study agents is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breast-feeding are not eligible for enrollment. 
 
 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Prohibited medications associated with olaparib are shown in Table 26. Restricted concomitant 
medications associated with olaparib are shown in Table 27.  
 
6.6.1 OLAPARIB 
 

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Table 27. Restricted concomitant medications - Olaparib 
Medication/class of drug: 
Usage (including limits for duration permitted 
and special situations in which it’s allowed ): 
Strong CYP3A inhibitors: 
itraconazole, telithromycin, clarithromycin, 
boosted protease inhibitors, indinavir, 
saquinavir, nelfinavir, boceprevir, 
telaprevir 
 
Moderate CYP3A inhibitors: 
ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil  
 
Strong or moderate CYP3A inhibitors should not 
be taken with olaparib.  If there is no suitable 
alternative concomitant medication then the 
dose of olaparib should be reduced for the 
period of concomitant administration. The dose 
reduction of olaparib should be recorded in the 
CRF with the reason documented as 
concomitant CYP3A inhibitor use.  
• Strong CYP3A inhibitors – reduce the dose of 
Olaparib to 100 mg twice daily for the duration 
of concomitant therapy with the strong 
inhibitor and for 5 half-lives afterwards. 
• Moderate CYP3A inhibitors - reduce the dose 
of olaparib to 150 mg twice daily for the 
duration of concomitant therapy with the 
moderate inhibitor and for 3 half-lives 
afterwards. 
After the washout of the inhibitor is complete, 
the olaparib dose can be re-escalated. 
Table 26. Prohibited medications - Olaparib - 
Prohibited medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed) 
Anticancer therapy: 
Chemotherapy 
Immunotherapy 
Monoclonal Antibodies against CTLA-4, 
PD-1, or PD-L1 other than those under 
investigation in this study 
Hormonal therapy* 
Radiotherapy (except palliative) 
Biological therapy 
Other novel agents 
Not permitted while the participant is receiving study 
medication 
CYP2C19  
lansoprazole, omeprazole, S-mephenytoin 
P-gp 
simvastatin, pravastatin, digoxin, dabigatran, 
colchicine 
Live virus vaccines 
 
 
 
Live bacterial vaccines 
Not permitted while the participant is receiving study 
medication and during the 30 day follow up period.  
 
An increased risk of infection by the administration of 
live virus and bacterial vaccines has been observed 
with conventional chemotherapy drugs and the effects 
with olaparib are unknown. 
OCT2 - 
Serum creatinine 
OAT3 - 
Furosemide, methotrexate 
*Hormone Replacement Therapy (HRT) is acceptable 

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Table 27. Restricted concomitant medications - Olaparib 
Medication/class of drug: 
Usage (including limits for duration permitted 
and special situations in which it’s allowed ): 
Strong inducers: 
phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s 
Wort 
 
Moderate CYP3A inducers: 
bosentan, efavirenz and modafinil 
Strong or moderate CYP3A inducers should not 
be taken with olaparib. 
 
If the use of any strong or moderate CYP3A 
inducers are considered necessary for the 
participant’s safety and welfare this could 
diminish the clinical efficacy of olaparib. 
 
If a participant requires use of a strong or 
moderate CYP3A inducer then they must be 
monitored carefully for any change in efficacy of 
olaparib 
• 
CYP3A4 substrates: hormonal 
contraceptive, simvastatin, cisapride, 
cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and 
quetiapine 
• 
CYP2B6 substrates: bupropion, 
efavirenz 
• 
OATP1B1substrates: bosentan, 
glibenclamide, repaglinide, statins and 
valsartan 
• 
OCT1, MATE1 and MATE2K 
substrates:  metformin 
• 
OCT2 substrates: serum creatinine 
• 
OAT3 substrates: furosemide, 
methotrexate 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may 
increase the exposure to substrates of CYP3A4, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and 
MATE2K. 
 
Based on limited in vitro data, olaparib may 
reduce the exposure to substrates of 2B6. 
Caution should be observed if substrates of 
these isoenzymes or transporter proteins are co-
administered. 
 
Anticoagulant therapy 
Participants who are taking warfarin may 
participate in this trial; however, it is 
recommended that international normalized ratio 
(INR) be monitored carefully at least once per 
week for the first month, then monthly if the INR 
is stable. Subcutaneous heparin and low 
molecular weight heparin are permitted. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the 
treatment of pain at the site of bony metastases 
that were present at baseline, provided the 
investigator does not feel that these are 
indicative of clinical disease progression during 
the study period.  Study treatment should be 
discontinued for a minimum of 3 days before a 
participant undergoes therapeutic palliative 
radiation treatment.  Study treatment should be 
restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.   

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Table 27. Restricted concomitant medications - Olaparib 
Medication/class of drug: 
Usage (including limits for duration permitted 
and special situations in which it’s allowed ): 
Administration of other anti-cancer agents 
 
Participants must not receive any other 
concurrent anti-cancer therapy, including 
investigational agents, while on study treatment. 
Participants may continue the use of 
bisphosphonates or denosumab for bone 
disease and corticosteroids for the symptomatic 
control of brain metastases provided the dose is 
stable before and during the study and they were 
started at least 4 weeks prior to beginning study 
treatment.  
 
6.6.2 DURVALUMAB 
 
Prohibited medications associated with durvalumab are shown in Table 28.  
 
Table 28. Prohibited Concomitant Medications - Durvalumab 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy 
other than those under investigation in this 
study  
Should not be given concomitantly whilst the 
participant is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
participant is on study treatment 
Any concurrent chemotherapy, 
radiotherapy, immunotherapy, or biologic 
or hormonal therapy for cancer treatment 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
participant is on study treatment. (Concurrent 
use of hormones for non-cancer-related 
conditions [e.g., insulin for diabetes and 
hormone replacement therapy] is acceptable. 
Local treatment of isolated lesions, excluding 
target lesions, for palliative intent is acceptable 
[e.g., by local surgery or radiotherapy]) 

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Table 28. Prohibited Concomitant Medications - Durvalumab 
Prohibited medication/class of drug: 
Usage: 
Immunosuppressive medications 
including, but not limited to, systemic 
corticosteroids at doses exceeding <<10 
mg/day>> of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers 
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions: 
• 
Use of immunosuppressive medications for 
the management of IP-related AEs,  
• 
Use in participants with contrast allergies.  
• 
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be 
essential for the management of non-
immunotherapy related events experienced by 
the participant (e.g., chronic obstructive 
pulmonary disease, radiation, nausea, etc.). 
EGFR TKIs <<unless the study is 
assessing the combination of an EGFR 
TKI and durvalumab>> 
Should not be given concomitantly. 
Should be used with caution in the 90 days post 
last dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence 
of transaminase increases (with 1st generation 
EGFR TKIs) has been reported when 
durvalumab has been given concomitantly. 
Live attenuated vaccines 
Should not be given through 30 days after the 
last dose of IP (including SoC) 
Herbal and natural remedies which may 
have immune-modulating effects 
Should not be given concomitantly unless 
agreed by the investigator 
 
6.6.3 CAPIVASERTIB 
 
6.6.3.1 
Drugs that may influence capivasertib pharmacokinetics 
 
Based on results from in vitro studies, capivasertib is primarily metabolised by CYP3A4 and 
UGT2B7 enzymes. Therefore, inhibitors or inducers of these enzymes may increase or 
decrease exposure, respectively, to capivasertib. The potent inducer enzalutamide reduced the 
systemic exposure to capivasertib by approximately 50%. There are no other confirmed clinical 
drug interactions with capivasertib. The potential interactions are considered on the basis of 
non-clinical data and physiology-based PK modelling. 
 
Strong inhibitors and strong inducers of CYP3A4 must not be combined with capivasertib and 
must be stopped at least 2 weeks before the first dose of capivasertib (3 weeks for St John’s 
Wort and 4 weeks for enzalutamide). Strong inhibitors must not be used for 2 days following 
discontinuation of capivasertib. Moderate inhibitors and inducers of CYP3A4 or UGT2B7 
inhibitors and inducers are permitted, but caution should be exercised and participants 
monitored closely for possible drug interactions. Drugs known to be inhibitors and inducers of 
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and a similar restriction will apply to other agents that are known to modulate CYP3A4 activity.  
Appropriate medical judgment is required.  Investigators are directed to contact sponsor-PI with 
any queries you have on this issue.   
 
Table 30. Drugs known to be strong or moderate inducers of CYP3A 
Must be stopped 2 weeks (3 weeks for St John’s 
Wort)prior to capivasertib administration. Must not be 
used concomitantly with capivasertib. 
Drugs are permitted but caution 
should be exercised and participants 
monitored closely for possible drug 
interactions: 
Table 29. Drugs known to be inhibitors of CYP3A4 or UGT2B7 
Must be stopped 2 weeks prior to capivasertib 
administration. Must not be used concomitantly with 
capivasertib and for 2 days following discontinuation 
of capivasertib: 
Drugs are permitted but caution 
should be exercised and participants 
monitored closely for possible drug 
interactions: 
Strong CYP3A4 inhibitors 
boceprevir 
clarithromycin (+TdP risk) 
cobicistat 
danoprevir and ritonavira 
elvitegravir and ritonavira 
indinavir and ritonavira 
itraconazole 
ketoconazole 
lopinavir and ritonavira 
nefazodone 
nelfinavir 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)a 
posaconazole 
ritonavira 
telaprevir 
telithromycin 
tipranavir and ritonavira 
troleandomycin 
voriconazole 
Moderate CYP3A4 inhibitors 
aprepitant 
ciprofloxacin (+TdP risk) 
cyclosporine 
diltiazem 
erythromycin (+TdP risk) 
fluconazole (+TdP risk) 
fluvoxamine  
tofisopam 
verapamil 
 
Strong or Moderate CYP3A4 inhibitors AND Sensitive 
CYP3A substrates  
Follow Guidance in Table 30: 
conivaptan 
dronedarone 
saquinavira 
UGT2B7 inhibitors 
cannabidiolb 
a. 
Ritonavir has dual effects of simultaneous CYP3A inhibition and induction; the net pharmacokinetic outcome 
during chronic ritonavir therapy is inhibition of CYP3A activity. Ritonavir is usually given in combination with 
other protease inhibitors. Please refer to the full Prescribing Information for these drugs prior to co-
administration with capivasertib. 
b. 
Cannabidiol is also a CYP3A4 substrate. 
c. 
CYP=Cytochrome P450 
TdP risk= Known risk of Torsades de Pointes according to the Arizona Centre for Education and Research on 
Therapeutics (ArizonaCert) website (https://www.crediblemeds.org/). Consider additional ECG monitoring. 

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Strong CYP3A inducers 
carbamazepine 
phenytoin 
rifampicin/rifampin 
St. John’s wort 
Moderate CYP3A inducers 
bosentan 
efavirenz 
etravirine 
phenobarbital 
primidone 
 
6.6.3.2 
Drugs that may be influenced by capivasertib 
 
There are currently no clinical data confirming that there are any PK interactions between 
capivasertib and drugs metabolised by CYP450 enzymes. Likewise, there are no confirmed 
interactions with renal or hepatic transporter substrates. The potential interactions are 
considered on the basis of preclinical data and physiology-based PK modelling. These suggest 
that capivasertib may be a moderate to strong inhibitor of CYP3A4, but a less potent inhibitor of 
some drug transporters and may thus increase the exposure of some drugs. Capivasertib also 
inhibited CYP2D6 and CYP2C9 in vitro. However, based on physiology-based PK modelling, 
the increase in exposure of sensitive substrates for these isoenzymes is not predicted to be 
clinically relevant (<10%). 
 
The guidance in Table 31 and Table 32 are based on the predicted magnitude of increase in 
exposure and the expected clinical significance of that increase (therapeutic window and/or QT 
liability). The lists are not intended to be exhaustive, and similar restrictions will apply to other 
agents that are known to be sensitive to inhibition of CYP3A or transporter proteins. Please 
refer to the full Prescribing Information for all drugs prior to co-administration with study 
intervention and consider dose reduction where clinically applicable. 
 
Table 31. Drugs known to be sensitive or moderate sensitive CYP3A substrates whose 
exposure, pharmacological action, and toxicity may be increased by capivasertib 
Must be stopped 1 week prior to capivasertib 
administration. Must not be used concomitantly 
with capivasertib and for 1 week following 
discontinuation of capivasertib. 
Drugs are permitted but caution should be 
exercised and participants monitored 
closely for possible drug interactions. 
Sensitive substrates 
alfentanil 
avanafil 
conivaptan 
dronedarone 
eletriptan 
eplerenone 
ivabradine 
lomitapide 
lovastatin 
lurasidone  
naloxegol 
 
nisoldipine 
quetiapine 
saquinavira 
simvastatin 
sirolimus 
tacrolimus 
ticagrelor 
tolvaptan 
triazolam 
vardenafil 
Sensitive substrates 
budesonide 
buspirone 
darifenacin 
darunavira  
ebastine 
felodipine 
indinavira 
maraviroc 
midazolam 
sildenafil 
tipranavira 

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Table 31. Drugs known to be sensitive or moderate sensitive CYP3A substrates whose 
exposure, pharmacological action, and toxicity may be increased by capivasertib 
Must be stopped 1 week prior to capivasertib 
administration. Must not be used concomitantly 
with capivasertib and for 1 week following 
discontinuation of capivasertib. 
Drugs are permitted but caution should be 
exercised and participants monitored 
closely for possible drug interactions. 
Moderate sensitive substrates 
alprazolam 
atorvastatin 
eliglustat 
pimozide (+TdP risk) 
Moderate sensitive substrates 
amlodipine 
aprepitant 
buprenorphine 
codeine 
colchicine 
fentanyl 
haloperidol 
methylprednisolone 
oxycodone 
rivaroxabanb 
sertraline 
tadalafil 
a Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. No clinically 
significant  additional increase in exposure is expected by capivasertib when combined with ritonavir. 
b Rivaroxaban must not used concomitantly with both capivasertib and P-gp inhibitors.  
CYP= Cytochrome P450; TdP risk= Known risk of Torsades de Pointes according to the Arizona 
Centre for Education and Research on Therapeutics (ArizonaCert) website 
(https://www.crediblemeds.org/). Consider additional ECG monitoring. 
 
Table 32. Drugs known to be substrates for renal or hepatic transporters whose 
exposure, pharmacological action, and toxicity may be increased by capivasertib 
Drug  
Advice 
Transporters involved  
dofetilide 
Drug is permitted but caution should be 
exercised and participants monitored 
closely for possible drug interactions. 
MATE1 and OCT2 substrate with a TdP 
risk 
metformin 
Metformin is currently the preferred oral 
anti-diabetic recommended for the 
management of hyperglycaemia 
occurring in participants enrolled in 
studies of capivasertib (see Section 
6.3.4.2 for further guidance). 
MATE, MATE-2K and OCT2  
pitavastatin 
pravastatin 
rosuvastatin 
Drugs are permitted but caution should 
be exercised and participants monitored 
closely for possible drug interactions. 
OATP1B1  
procainamide 
Drugs are permitted but caution should 
be exercised and participants monitored 
closely for possible drug interactions. 
OCT2 substrate with a TdP risk 
 \* MERGEFORMAT  
6.6.3.3 
Capivasertib Precautions Regarding QTc-prolongation Medications 
 
Due to the important potential risk of QT prolongation derived from the capivasertib non-clinical 
development programm, it is recommended that administration of any drugs (at screening or 
during study conduct) considered essential for patient management which are known to prolong 

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the QT interval is discussed with the Study PI (in consultation with AZ study physician, if 
indicated) and that consideration should be given for close monitoring of QT interval 
prolongation through frequent ECG and electrolyte monitoring.  See Table 31 for additional 
guidance regarding drugs known to prolong the QT interval and that are at risk for a potential 
pharmacokinetic interaction with capvasertib.  
 
Please refer to the following sites for further information on inhibitors, inducers and substrates.  
• 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm  
• 
https://didb.druginteractionsolutions.org/  
 
6.6.4 SELUMETINIB 
 
6.6.4.1 
Selumetinib Precautions Regarding CYP-interacting Medication 
 
Unless considered clinically indicated, participants should avoid changes to or the addition of 
concomitant medications that may affect the metabolism of selumetinib, including CYP2C19, or 
3A4 moderate/strong inhibitors/ inducers (summarized in Appendix H). There are no dose 
reduction recommendations for selumetinib if these concomitant medication cannot be avoided.  
 
During the studies, participants should avoid consuming large amounts of grapefruits, Seville 
oranges, or any other products that may contain these fruits (e.g., grapefruit juice) as these may 
effect selumetinib metabolism. 
 
6.6.4.2 
Vitamin E intake 
 
Selumetinib capsules contain vitamin E in the form of TPGS, a water-soluble form of vitamin E, 
which acts as a formulation excipient.  The maximum daily dose of vitamin E that a study 
subject may receive from selumetinib is approximately 261.6 mg/day. Therefore,- 
• 
participants should not take any supplemental vitamin E. High doses of vitamin E have 
been reported to cause bleeding and interfere with blood coagulation processes. 
• 
Selumetinib should be administered with caution in participants who are also receiving 
concomitant coumarin anticoagulant medications (e.g. warfarin). These participants 
should have their INR monitored / anticoagulant assessments conducted more 
frequently and the dose of the anticoagulant should be adjusted accordingly.  
 
6.6.4.3 
Oral Hygeine 
 
Participants should be made aware of the need for good oral care while receiving selumetinib. 
Refer to Section 6.6.4.3.  
 
6.6.5 CERALASERTIB 
 
Ceralasertib is an investigational drug for which no data on in vivo interactions are currently 
available. Potential interaction is considered on the basis of preclinical in vitro data only.  
 
The lists of CYP and transporter inhibitors/inducers, and CYP and transporter substrates are 
available below. They are not exhaustive and the absence of a drug from these lists does not 
imply that its combination with ceralasertib is safe. If ceralasertib is being administered in 
combination, potential interactions of the combination partner should also be considered. 

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6.6.5.1 
Ceralasertib Precautions Regarding CYP-interacting Medication 
 
There are currently no data confirming that there is a pharmacokinetic (PK) interaction between 
these agents and ceralasertib; a potential interaction is considered on the basis of preclinical 
and in vitro data only. Ceralasertib is predominantly eliminated via CYP3A metabolism, 
therefore CYP3A inhibitors or inducers may increase or decrease exposure to ceralasertib, 
respectively.  
Potent inhibitors or inducers of CYP3A should not be combined with ceralasertib. In vitro data 
also suggest that ceralasertib may be metabolised by CYP2C8 but a lesser extent, therefore 
caution should be applied with co administration of potent inhibitors or inducers of CYP2C8.  
 
Potent inhibitors or inducers of CYP3A should not be combined with ceralasertib (refer to 
Appendix H).  These lists are not intended to be exhaustive, and similar restrictions will apply to 
other agents that are known to modulate CYP3A or CYP2C8 activity. Please contact 
AstraZeneca with any queries you have on this issue. Please refer to full prescribing information 
for all drugs prior to co-administration with ceralasertib. 
 
6.6.5.2 
Ceralasertib Precautions Regarding Pgp inhibitors/inducers and/or BCRP inhibitors 
 
Ceralasertib is a substrate of Pgp and BCRP.  Co-administration of Pgp inhibitors/inducers or 
BCRP inhibitors/inducers may affect exposure to ceralasertib; therefore, it is recommended that 
these are not co-administered with ceralasertib.  Agents listed are not intended to be 
exhaustive, and similar restrictions will apply to other agents that are known to modulate Pgp 
activity or BCRP activity (refer to Appendix H). 
 
6.6.5.3 
Ceralasertib Precautions Regarding OATP1B1 and BCRP Substrates 
 
Ceralasertib is also an inhibitor of OATP1B1 and BCRP. Caution should be applied with 
coadministration of substrates of OATP1B1 and/or BCRP as ceralasertib may increase their 
exposure (refer to Appendix H). 
 
 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
• 
The use of any natural/herbal products (including cannabis) or other traditional remedies 
should be discouraged, but the use of these products, as well as any medication or vaccine 
including over-the-counter or prescription medicines, vitamins, and/or herbal supplements 
that the participant is receiving at the time of enrolment or receives during the study must be 
recorded along with: 
o Reason for use 
o Dates of administration including start and end dates 
o Dosage information including dose and frequency 
• 
Participants should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab.  
• 
Live vaccines within 30 days prior to the first dose of study drug and while on study. 
Examples of live vaccines include, but are not limited to the following: measles, mumps, 
rubella, chickenpox, yellow fever, rabies, BCG, and typhoid (oral) vaccine.  

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o Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines and are not allowed. Vaccines for SARS-CoV-2 (i.e., COVID-19) are permitted.  
• 
Immunosuppressive medications including, but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers. 
• 
Drugs with laxative properties and herbal or natural remedies for constipation. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management may be removed from the trial. Participants 
may receive other medications that the investigator deems to be medically necessary. 
 
Participant exclusion criteria (Section 4.2) describes other medications prohibited in this trial. 

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7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE  
 
 
STUDY SPECIFIC PROCEDURES 
 
7.1.1 MEDICAL HISTORY  
 
A medical history will be obtained by the investigator or qualified designee. In addition to 
collecting information on demographics, the medical history will include all active conditions, and 
any condition diagnosed within the prior 10 years that are considered to be clinically significant 
by the Investigator. Details regarding the participant’s TNBC will be recorded separately and not 
listed as medical history. 
 
7.1.2 DISEASE ASSESSMENT 
 
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s breast cancer. 
 
7.1.3 MEDICATION HISTORY  
 
A complete medication history will be acquired concurrently with medical history.  
 
7.1.4 PHYSICAL EXAMINATION  
 
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant, or Advanced Registered Nurse Practitioner as local law 
permits and per institutional standards.  The physical examination to be conducted will include 
an evaluation of: general appearance; head, ears, eyes, nose, and throat; neck; skin; 
cardiovascular system; respiratory system; gastrointestinal system; lymphatic system, 
musculoskeletal system, and nervous system. All other physical exams after baseline will 
include an evaluation of any AEs, or any previously reported symptoms, or prior physical 
examination findings.  All physical examinations will also include: 
 
7.1.4.1 
Vital signs  
 
Vitals to be collected include blood pressure (BP), heart rate (HR), temperature, and oxygen 
saturation by pulse oximetry. As part of the screening/baseline visit, vitals should be obtained 
within 10 days prior to the first dose of study agent. Vitals will also be obtained during treatment.  
 
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History eCRF page. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event eCRF page.  
 
7.1.4.2 
Height and weight  
 
Height will be collected at screening only.  Weight will be collected at each visit.  
 
7.1.4.3 
Performance status  
Performance status will be determined for all participants at screening and at select times during 
treatment as per the assessment schedule in Section 7.14.  Refer to Appendix C for 
performance criteria. 
 

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7.1.5 ELECTROCARDIOGRAM (ECG)  
 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study.  ECGs should be obtained after the participant has been in a supine position and 
recorded while the participant remains in that position. 
 
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 
12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.   
 
Situations in which ECG results should be reported as AEs are described in Section 10.1.1 
At Screening, a single ECG will be obtained on which QTcF must be <470 ms.  
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 
12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.  
Situations in which ECG results should be reported as AEs are described in Section 9.1.  
 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules  
 
7.1.5.1 
Selumetinib arm (only) 
 
An ECG assessment is not required if taken within 14 days of the screening ECG and the 
participant’s condition has not changed (no new treatment during this period of time with no new 
complication or aggravation). 
 
Single ECGs should be performed at the time of significant LVEF drop (Section 6.3.5.8) and on 
occurrence of any cardio respiratory adverse event with no obvious diagnosis.  For patients with 
new or worsening respiratory symptoms (such as dyspnea, cough), an ECG is recommended 
and additionally at the discretion of the Investigator if clinically indicated. 
 
7.1.5.2 
Capivasertib arm (only) 
 
For participants assigned to receive capivasertib, an ECG should be performed pre-dose and 1-
2 hours post-dose on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and every 12 weeks 
thereafter, as clinically indicated, at end of treatment visit(s) and 30 days post last dose of 
capivasertib. 
 
7.1.6 ECHOCARDIOGRAM (ECHO)/MULTI-GATED ACQUISITION (MUGA) SCAN 
 
A baseline MUGA/ECHO should be performed at screening for all participants, and thereafter 
only as clinically indicated. For participants assigned to Arm 2 (selumetinib) or Arm 3 
(capivasertib), additional scans are required as follows: 
 
Arm 2 (selumetinib)  –MUGA/ECHO assessment shoud be performed every 3 months while 
receiving selumetinib.   
 
Arm 3 (capivasertib) - MUGA/ECHO assessment should be performed as clinically indicated 
while receiving capivasertib.  
 
7.1.7 MEDICAL DIARY 
 
Participants that self-administer oral study agents (e.g., olaparib) are required to maintain a 
medication diary to assess compliance.  Participants will receive instruction on how to 

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administer study drug from a physician, clinical research nurse, or other designated, qualified 
healthcare provider.  Participants will be provided with a medical diary and are required to 
record the date, dose, and the time of the ingestion. 
 
7.1.8 ADVERSE EVENT EVALUATION  
 
Toxicities and adverse experiences will be assessed at each visit using the NCI CTCAE 5.0. 
Safety will be monitored by assessing physical examination, vital signs, body height (screening 
only) and weight, performance status, hematology, chemistry, coagulation, urinalysis, thyroid 
function, and pregnancy, as well as collecting of AEs at every visit. 
 
Adverse events will be monitored from the time the participant receives treatment on study.  
Participants will be instructed to report all AEs during the study and will be assessed for the 
occurrence of AEs throughout the study, including and up to 3 months following completion of 
study therapy.  All AEs (serious and non-serious) must be recorded on the source documents 
and eCRFs regardless of the assumption of a causal relationship with the study drug.  
 
Abnormal laboratory values will only be recorded as an AE if determined to be clinically 
significant by the investigator. 
 
For details on AE collection and reporting, refer to Section 9. 
 
7.1.9 EYE EXAMINATION (SELUMETINIB TREATMENT ARM ONLY) 
 
For participants assigned to receive selumetinib, an ophthalmologic examination (best corrected 
visual acuity, intraocular pressure and slit lamp fundoscopy) should be performed at screening 
and as clinically indicated whilst the participant is on study drug.  
 
If a participant experiences AE/symptoms of visual disturbance (including blurring of vision) a 
complete ophthalmological examination, including a slit-lamp examination, must be performed.  
 
If an abnormality is detected, fundus photography and an OCT scan can also be performed 
where required. AEs are to be managed accordingly to Section 6.3.5.2.  If retinal abnormality 
prior to or at the time of selumetinib discontinuation has been observed a repeat 
ophthalmological examination is to be performed 30 days after discontinuation of selumetinib in 
order to document reversibility. 
 
 
RADIOGRAPHIC OR OTHER IMAGING ASSESSMENTS  
 
Tumor imaging may be performed by computed tomography (CT) (preferred),  magnetic 
resonance imaging (MRI), or Fluorodeoxyglucose (18F)-positron emission tomography (PET) 
may be used if clinically indicated.  Likewise, if clinically indicated, bone scans will also be 
utilized to assess osseous metastases.  Plain X-ray evaluation may also be obtained for 
symptomatic sites with negative bone scan evaluations.   
 
Radiographic imaging for disease assessment will follow standard of care and be performed 
according to institutional guidelines.  Imaging should be performed according to Schedule of 
Events (Section 7.14); however, more frequent imaging is allowed if clinically indicated.   
 
Initial tumor imaging must be performed within 28 days prior to the first dose of trial treatment. 
Scans performed as part of routine clinical management are acceptable for use as the 

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screening scan if they are of diagnostic quality, meet the requirements specified in the imaging 
manual, and performed within 28 days prior to the first dose of trial treatment.   
 
After completing on-study therapy, the results of subsequent imaging assessments will be 
captured as part of study follow-up.  
 
7.2.1 COMPUTED TOMOGRAPHY 
 
Tumor imaging may be performed by CT, as clinically indicated, according to institutional 
guidelines.  
 
7.2.2 MRI 
 
MRI may be performed according to institutional guidelines.   
 
7.2.3 BONE SCANS 
 
99mTc -methylene diphosphonate (MDP) bone scintigraphy is not required.  Participants with 
positive bone scans at baseline may be followed as clinically indicated with additional scans.  A 
bone scan may be obtained for participants with new symptoms concerning of osseous 
metastasis (e.g., new persistently elevated alkaline phosphatase).  Additionally, plain X-ray 
evaluation should be obtained for symptomatic sites with negative bone scan evaluations.  New 
osseous uptake, upon confirmation with CT or per institutional standard, will be assessed for 
progression per RECIST 1.1.  Lytic/mixed lesions with soft tissue component may be included in 
the evaluation of disease burden if it meets measurability criteria, while blastic lesions are 
considered non-measurable, in accordance with RECIST 1.1. 
 
7.2.3.1 
Dose administration  
 
Dose administered should be according to standard weight-based protocols. Injection site 
should be away from lesion extremity or contralateral extremity if flow imaging is to be 
performed. Three-phase imaging is not required unless warranted by symptoms for a focal 
lesion to assess hyperemia. 
 
7.2.3.2 
Imaging parameters 
 
Whole body delayed imaging is acquired 2-3 hours after injection of the radiopharmaceutical. 
Spot views should be acquired of specific sites of symptoms or of any sites of abnormality as 
warranted by the whole body views. 
 
7.2.4 POSITRON EMISSION TOMOGRAPHY (PET) 
 
18F-PET imaging is optional but is encouraged for all participants. The primary lesion must be ≥ 
1 cm on baseline anatomic imaging in order for an FDG-PET scan to be performed.   
 
7.2.4.1 
Participant Guidelines 
 
The participant should fast for at least 4 hours prior to injection of 18F.  18F -PET imaging may 
follow a multi-gated acquisition scan (MUGA) study on the same day, or 18F-PET imaging may 
be performed on the day preceding this study. Plasma glucose should be checked and, if the 
participant is hyperglycemic (plasma glucose > 250 mg/dL), appropriate treatment with small 

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doses of insulin may be given to bring the plasma glucose into the normal range prior to 18F -
PET imaging. However, insulin administration may result in excessive muscle uptake of 18F and 
consequent tumor non-visualization. If possible, the study should be postponed until the plasma 
glucose is under better control. 
 
Good hydration is required, as the primary route of 18F excretion is renal. The participant should 
drink water or receive intravenous fluids (not containing dextrose) after 18F injection to promote 
urinary excretion of the radioactive substrate. After injection, the participant must be kept in a 
resting state for 45-60 minutes prior to imaging. The participant should empty the bladder 
immediately prior to imaging. 
  
7.2.4.2 
Imaging Technique  
 
The technique will vary by local institutional guidelines. In general, 18F is administered 
intravenously at a dose of 0.125-0.200 mCi/kg or by algorithms that adjust the dose by body 
surface area, with a minimum total dose of 2.0 mCi and maximum total dose of 20.0 mCi.  
 
The body should be imaged from the top of the ears to the bottom of the feet. If there is 
suspicion of involvement of the skull or skull contents, the volume that is imaged should be 
expanded.  
 
Imaging with a dedicated PET/CT camera is standard.  
 
The length of time needed to perform head to toe CT will depend on the participant’s height but 
will be approximately 45 seconds. Contiguous axial images should be obtained at 5 mm 
thickness using 90 mA and 120 Kv and adjusted for local institutional protocol. No oral or IV 
contrast is required, but either or both are permissible and may be of benefit in cases where 
intraabdominal or pelvic pathology is a specific concern. With regard to participant positioning, 
the arms can be placed in a comfortable position at the participant’s sides as long as they fit into 
the field of view. If the participant is large, it may be necessary to lay the arms across the 
abdomen and hold in position with a stabilizing device. 
  
7.2.4.3 
Study Processing  
 
The 18F-PET study is processed for display by an iterative reconstruction algorithm.  18F activity 
should be corrected for attenuation, scatter, and radioactive decay. Attenuation correction is 
necessary, as apparent uptake will otherwise vary with depth of the lesion in the body and the 
nature of surrounding tissues. The procedure used for attenuation correction should be 
recorded. The level of tumor uptake is assessed subjectively by visual inspection and semi-
quantitatively by determination of standardized uptake values (SUV). Uptake time, glucose 
levels, and partial volume effects influence both methods. The SUV method is also dependent 
on body weight, and correction of SUV by normalizing for body surface area (BSA) reduces this 
dependency on body weight. SUVs should be calculated for lesions known to be 1.2 cm or 
larger in diameter. Smaller lesions may have underestimated SUVs due to partial volume 
averaging effects at typical scanner resolutions (0.6-1.2 cm). 
  
To calculate the SUV, a region of interest (ROI) should be carefully drawn around as much of 
the area of elevated 18F uptake as can be done. The SUV should be calculated as SUVBSA = 
ROI activity concentration (nCi/cc) x BSA / injected activity (nCi). SUVMAX is obtained by 
determining the activity of the pixel with the highest 18F uptake. 

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LABORATORY PROCEDURES AND EVALUATIONS 
 
Refer to Section 7.14 for a schedule of all laboratory test and procedures. 
 
7.3.1 HEMATOLOGY 
 
Hematologic profiling will be collected per institutional standards and should include evaluation 
of hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. 
 
7.3.2 BIOCHEMISTRY  
 
Blood chemistry will be collected per institutional standards and should include the following:  
 
• Albumin 
• Alkaline phosphataseA 
• Alanine aminotransferaseA 
• Aspartate aminotransferaseA 
• Bicarbonate  
• Calcium 
• Chloride 
• Creatinine  
• Creatinine PhosphokinaseB 
• Glucose 
• HbA1cC 
• Total bilirubinA 
• Serum or plasma troponin I or TC 
• Serum or plasma lipidsC 
• Free T3 or free T4D 
• Total protein 
• Total cholesterol and 
triglycerides 
(fasted)C 
• Magnesium 
• Potassium 
• Sodium  
• Urea or blood urea 
nitrogen, depending 
on local practice 
• Serum glucose 
(fasted)C 
A Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If total 
bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into direct and indirect 
bilirubin. 
 In case a participant shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN please refer to 0 ‘ 
Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law (Appendix G), for further 
instructions 
B Only required only for those receiving selumetinib, or as clinically indicated 
C Only required only for those receiving capivasertib, or as clinically indicated  
D Free T3 or free T4 should only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to 
the endocrine system  
 
For screening only (all participants): Hepatitis B (e.g., HBsAg reactive), Hepatitis C (e.g., HCV 
Ab, HCV RNA), and HIV (HIV antibody, HIV RNA) status. For individuals with controlled HIV, 
results of CD4+ T-cell count and viral load derived from clinical reports in the past 3 months prior 
to study entry are acceptable. Amylase, Lipase, Lactate dehydrogenase.  
 
For Arm 3 (capivasertib only) - total cholesterol and triglycerides (fasted): Total cholesterol and 
triglycerides (fasted) to be performed at screening and every 12 weeks thereafter, as clinically 
indicated, at end of treatment visit(s) and 30 days post last dose of capivasertib. 
 
For Arm 3 (capivasertib only) – serum glucose (fasted): Serum glucose (fasted) to be performed 
at screening, pre-dose and 2 (+2) hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 
15, pre-dose on Day 1 of each subsequent cycle, as clinically indicated, at end of treatment 
visit(s) and 30 days post last dose of capivasertib. 
 

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For Arm 3 (capivasertib only) – Serum glycosylated hemoglobin (HbA1c) to be performed at 
screening, and every 12 weeks thereafter and as clinically indicated. 
 
7.3.3 TUMOR MARKERS 
 
Carcinoembryonic antigen (CEA), cancer antigen 15-3 (CA 15-3), and cancer antigen 27-29 (CA 
27-29) will be collected as per the schedule of events (Section 7.14). 
 
7.3.4 URINALYSIS  
 
A baseline urinalysis should be performed at screening for all participants: color and 
appearance, glucose, protein, hemoglobin (blood), bilirubin, ketones, pH, and specific gravity.  A 
microscopic exam should be performed for 2+ (~0.5 to 1.5 g/24 hours) or higher hemoglobin or 
protein levels.  
 
For Arm 3 (capivasertib only) - urinalysis assessments to be performed at screening, Cycle 1 
Day 1, Day 15, at Day 1 of each subsequent cycle, as clinically indicated, at end of treatment 
visit(s) and 30 days post last dose of capivasertib. 
 
7.3.5 COAGULATION PANEL 
 
Activated partial thromboplastin time (APTT) will be performed at screening and if clinically 
indicated.  
 
International normalized ratio (INR) will be performed at screening and if clinically indicated. 
Participants taking warfarin may participate in this study; however, it is recommended that INR 
be monitored carefully at least once per week for the first month, then monthly if the INR is 
stable. 
Each coagulation test result will be recorded in the appropriate eCRF. 
 
7.3.6 PREGNANCY TEST 
 
Pregnancy tests on blood or urine samples will be performed for participants of childbearing 
potential within 28 days prior to the start of study treatment, on Day 1 of the study prior to 
commencing treatment, on Day 1 of each subsequent treatment cycle, and at the 30 day follow 
up visit.  Serum pregnancy test at time of screening is preferred, but urine test is acceptable.  
Tests will be performed by the hospital’s local laboratory. If results are positive the participant is 
ineligible, and must be discontinued from study treatment immediately.  Details of the pregnancy 
tests must be recorded in the participant’s medical records.  
 
7.3.7 BONE MARROW OR BLOOD CYTOGENETIC SAMPLES 
 
Bone marrow or blood cytogenetic samples may be collected for participants with prolonged 
hematological toxicities, as defined in section 6.3.1.3. 
 
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic analysis 
and flow cytometry, and a core biopsy for bone marrow cellularity. If it is not possible to conduct 
cytogenetic analysis or flow cytometry on the bone marrow aspirate, then attempts should be 
made to carry out the tests on a blood sample. The investigator must provide full reports for 
documentation on the Participant Safety database. These data are not required to be entered 
into an eCRF. 

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BIOSPECIMEN COLLECTION 
 
All bio-specimens will be given a specimen identification number generated by OHSU's 
approved Biobank Enterprise Management System (BEMS) (refer to Section 12.3.4) and, 
possibly a study identification number.  Specimen tracking will occur within BEMS and the study 
records to maintain chain of custody.  Biospecimens may be labeled with identifying information 
in order to generate clinical reports.  All specimens BEMS identification numbers will be linked 
to a limited data set of clinical information with the only identifiers being dates of treatment, and 
participant age [date of birth] at time of treatment.  In this study, clinical data and excess bio-
specimens not distributed to research labs, as described in Appendix B will be stored for future 
research within the OHSU Biolibrary (refer to Section 12.3.5). 
 
Archival tissue and any previous assay or test results may also be acquired for analysis. For the 
purposes of this protocol, archival tissue is defined as any biospecimen collected prior to 
enrollment on this study (e.g., at initial or recurrence diagnosis).  Tissue may be from the 
primary site or metastases obtained during prior procedures.  The archived tissue sample may 
be formalin fixed and paraffin embedded (FFPE) blocks on file within the local pathology 
department or may require requesting biospecimens from the outside facility that performed the 
initial diagnostic procedure.  
 
7.4.1 TISSUE BIOPSY 
 
All participants will have the required core biopsies taken pretreatment and at 2 weeks after 
starting olaparib monotherapy (cycle 1 day 14 ± 7 days) for CLIA assays and exploratory 
studies.  A biopsy at the time of disease progression is optional, but not required.  Biopsy 
procedures will be performed according to institutional guidelines and may be excisional, 
incisional, or core needle (image guided recommended).  The investigator(s), in consultation 
with the radiology staff, must determine the degree of risk associated with the procedure and 
find it acceptable.  Biopsies may be done with local anesthesia or conscious sedation. 
Institutional guidelines for the safe performance of biopsies should be followed. Tumor biopsy 
should not be performed on Fridays, holidays, or the day before a 1 or 2-day holiday, or 
weekends. If overnight shipment is required, specimens must be shipped Monday-Thursday, 
except for holidays or the day before a holiday. Please refer to SMMART-AMTEC Laboratory 
Manual for shipping details.  
 
For fresh tumor biopsies, 7 core biopsies from an 18 gauge needle (or an equivalent amount of 
tissue) are recommended.  When possible, the tumor site biopsied should be different from any 
lesion that is being measured using RECIST v1.1 criteria.  Depending upon tissue availability, 
additional core biopsies may be preserved in additional formats for optional exploratory 
research analytics (refer to Appendix B). Details regarding the appropriate labeling, handling, 
and shipping of specimens are detailed in the SMMART-AMTEC Laboratory Manual. 
 
7.4.1.1 
Pre-treatment biopsy  
 
Pre-treatment tumor biopsy is required for all study participants.  Pre-treatment biopsy may be 
done during the screening period prior to study treatment start.   
 
7.4.1.2 
On-treatment Biopsy 
 

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On-treatment tumor biopsy at 2 weeks is required for all study participants.  Tissue biopsy must 
be collected on Day 14 of Cycle 1 (± 7days).   
 
Note: If the biopsy at 2-weeks yields insufficient tumor cells for the effective evaluation of 
planned analytics, the participant may either:  
1. Continue on the assigned therapy.  
2. Proceed immediately with a second biopsy. 
3. Go off study treatment and enter follow-up period (refer to Section 7.14). 
 
7.4.1.3 
Optional core biopsy at disease progression 
 
Following disease progression, tissue samples are optional and will be acquired in the same 
way as the on-therapy biopsies from participants who have consented.  If a surgical procedure 
is performed for a clinical indication or as part of a different research study, excess tumor tissue 
may be used for research purposes with the consent of the participant. 
 
7.4.2 BLOOD COLLECTION FOR RESEARCH 
 
Peripheral blood for hematology and serum biochemistry should be collected per institutional 
guidelines.  In most cases, blood samples for research purposes will be drawn from participants 
scheduled to have venipuncture for routine clinical purposes.  In some cases, when this is not 
possible, a research-only blood draw will be undertaken.  For this protocol, up to approximately 
60 mL of blood may be collected, dependent on participant’s status, for exploratory or clinical 
analytic per instance. Details regarding the appropriate labeling, handling, and shipping of blood 
samples are detailed in the SMMART-AMTEC Laboratory Manual. 
 
Blood will be collected at the time points outlined in the schedule of events (Section 7.14).   
 
7.4.2.1 
Blood for Clinical Analysis 
 
Peripheral blood will be collected for analysis by targeted DNA or whole exome sequencing. 
 
7.4.2.2 
Blood for Research Analytics 
 
Peripheral blood will be collected for exploratory research analytics (refer to Appendix B for 
additional details). Details regarding the specific amounts and tube types are detailed in the 
SMMART-AMTEC Laboratory Manual. 
 
7.4.3 FECAL SAMPLE COLLECTION 
 
i) Collection of Specimen(s) 
 
Participants will be requested to collect a stool sample up to 48 hours prior to the scheduled 
office visit.  This is an optional procedure, and participants' refusal will not impact their 
continued trial eligibility.  Samples are to be collected at screening, before starting 
durvalumab and at the time of disease progression.  Participants will be provided a labeled 
container for sample collection and given detailed instructions by a member of the study 
team on how to collect the sample.  Participants will be instructed to not fill the biospecimen 
container more than three-quarters full (i.e., to the indicated line on the label of the 
container).  Participants will be instructed to label the container with the date of collection, as 
well as any other information requested by the study team (e.g., diet requirements). 

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Biospecimens collected less than 4 hours prior to the scheduled visit can be stored at room 
temperature. Samples collected longer than 4 hours from the time of the visit must be stored 
at 4°C (maximum of 48 hours).  
 
ii) Handling of Specimens 
Specimens received from participants by the OHSU study team will be processed for DNA 
extraction and stored at -80°C until ready for analysis.  
 
iii) Sites Performing Correlative Study 
Knight Cancer Institute, Oregon Health & Science University; Portland, OR 
 
 
SMMART CLINICAL ANALYTICS PLATFORM 
 
The specific clinical analytics to be performed, under the SMMART Clinical Analytics Platform, 
on each participant sample will be dependent on sample availability and are subject to 
investigator discretion.  All Laboratory Developed Tests (LDTs) or FDA-approved In Vitro 
Diagnostic (IVD) assays comprising the SMMART Clinical Analytics Platform will be performed 
by a CLIA-licensed/CAP-accredited laboratory.  Potential clinical assays are detailed below.  
Unless otherwise stated, tumor tissue obtained from biopsies and peripheral blood will be routed 
through the KDL for appropriate processing and analysis of the described assays.  At the 
discretion of the investigator, additional clinical assays not offered by OHSU may be requested 
from other CLIA-certified/CAP-accredited laboratories. 
 
7.5.1 IMMUNOHISTOCHEMISTRY 
 
Immunohistochemistry (IHC) staining of individual protein targets will be will be sub-contracted by 
the KDL to OHSU Surgical Pathology the Histopathology Shared Resource (HSR) or, if 
necessary, other CLIA-certified/CAP-accredited laboratories.  IHC may be performed locally at 
each participating subsite and results provided to the OHSU coordinating center.  The profiled 
proteins will relate to characteristics that are intrinsic to the cancer cells, such as growth, survival, 
death, motility, and DNA repair, as well as those that are extrinsic, such as the immune system 
and tumor microenvironment. Protein biomarkers to be assessed by IHC may include: estrogen 
receptor (ER), progesterone receptor (PR), androgen receptor (AR), human epidermal growth 
factor receptor type 2 (HER2), markers of proliferation (Ki67), PD-L1, apoptotic regulators (BCL-
2), GATA binding protein 3 (GATA3), cluster designated (CD) 4 (CD4), CD8, and phosphatase 
and tensin homolog (PTEN).   
 
7.5.2 TARGETED DNA SEQUENCING 
 
Sequencing of a targeted panel of genes to identify clinically relevant genetic alterations will be 
performed on patient biospecimen at the KDL using the GeneTrails® Solid Tumor Panel. The 
assay will also identify microsatellite instability (MSI) and may also report an estimate of the 
tumor mutational burden (TMB). Updated or alternative targeted panels may be used as they 
become available or if clinically appropriate.  
 
7.5.3 WHOLE EXOSOME SEQUENCING 
 
Whole exome sequencing (WES) of a tumor/normal pair to identify genetic alterations. The KDL 
will sub-contract WES to Tempus Labs, Inc., a CLIA-compliant/CAP-accredited laboratory 
(CLIA# 14D21140007 and CAP# 9457450). Tempus Labs, Inc. will perform high throughput 
sequencing, report the results back to the KDL, and provide raw sequencing files for download 

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and analysis. Alternatively, another CLIA-certified/CAP-accredited laboratory or research use 
only (RUO) service provider may be utilized at investigator discretion.  Any results from a RUO 
service provider will not be used for clinical purposes or reported back to the participant. 
 
7.5.4 RNA SEQUENCING 
 
Sequencing of RNA isolated from patient biospecimen to characterize the transcriptome and 
identify fusions will be performed at the KDL or, if logistically necessary, another CLIA-
certified/CAP-accredited laboratory. Regardless, processing of the raw sequencing data into 
gene-level expression values, including read alignment, recalibration, and quantification will be 
performed utilizing a computational pipeline constructed by the OHSU Bioinformatics Core and 
the KDL. Dependent upon sample availability, additional RNA sequencing work may be 
performed by Tempus Labs, Inc., who will provide raw sequencing files for download and 
analysis. In some cases, such as those with extremely limited sample availability, transcriptome 
sequencing may be replaced with a more limited RNA sequencing assay such as the 
GeneTrails® Solid Tumor Fusion Gene panel which identifies clinically actionable fusions in a 
limited set of genes. 
 
7.5.5 PROTEIN PROFILING 
 
Multiplex protein profiling to measure the abundance and phosphorylation status of proteins will 
be performed on patient biospecimen at the KDL. Profiling assays such as the GeneTrails® 
Quantitative Intracellular Signaling Panel or Nanostring® GeoMx Digital Spatial Profiler will be 
used to measure proteins related to characteristics intrinsic to the cancer cells, such as growth, 
survival, death, motility, and DNA repair. Additional or alternative protein profiling assays may 
be used as they become available. 
 
 
SMMART EXPLORATORY RESEARCH ANALYTICS PLATFORM 
 
The specific exploratory assays performed on each patient sample will be dependent on sample 
availability, relevance to the scientific objectives of this study, and are subject to investigator 
discretion. These analytics will be performed or overseen by OHSU scientists affiliated with the 
SMMART Clinical Trials Program. Potential exploratory assays comprising these exploratory 
research analytics are detailed in Appendix B.   
 
OHSU scientists will conduct or oversee the analysis of clinical and exploratory assay results as 
well as the integration of these data with patient clinical metadata. In some instances, in order to 
accomplish their scientific objectives, OHSU scientists may work with internal or external 
collaborators or core facilities who provide essential expertise or capabilities. Study samples, 
data, or both may be released to co-investigators, collaborating institutions, and commercial 
laboratories for additional analyses aligned with achieving the aims of this study. All relevant 
policies and procedures for proper data and sample sharing will be followed, including 
requirements of de-identification of protected patient information or use of limited data set data. 
 
 
QUALITY OF LIFE (QOL) AND PATIENT-REPORTED OUTCOMES (PRO) 
 
Patient reported QOL will be assessed by two standard questionnaires, one for all cancer 
patients (QLQC30) and one specific to breast cancer (QLQBR23), both of which are 
recommended for inclusion in clinical trials in breast cancer patients.175-177  QLQC30 will be used 
to describe participant QOL at baseline and to assess changes in response to study 
interventions. Utility of QLQBR23 has been demonstrated in several breast cancer clinical trials.  

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In a longitudinal study, metastatic breast cancer patients, completion rates for both surveys 
administered seven times over a 24-month period were >80% with these instruments detecting 
clinically meaningful worsening of symptoms over time.178  
 
QLQC30 is a 30-item measure and yields scores for 5 functional scales (physical, role, 
cognitive, social, and emotional), 3-symptom scales (nausea, pain, and fatigue), a global health 
and QOL scale, and perceived financial impact of treatment.179  QLQC30 can distinguish 
patients according to performance status and is the most commonly used QOL instrument in 
oncology research.180,181 
 
QLQBR23 is a 23-item instrument that measures symptoms and side effects related to 
treatment, body image, sexuality, and future perspective specific to breast cancer patients. 
QLQBR23 has high internal consistency (Cronbach’s a = 0.71-0.90), can distinguish between 
patients based on disease stage, performance status, treatment modality, or prior surgery, and 
is sensitive to change over time.182 
 
QOL surveys will be collected at baseline and at times described in schedule of events.  
 
 
SCREENING ASSESSMENTS 
 
A screening (consultation) visit may occur as part of standard of care.  If a participant is eligible 
for the study after a review of key inclusion/exclusion criteria, additional screening visits will be 
scheduled while staff members are requesting insurance review for exclusions to participate in a 
clinical trial.  
The following will be reviewed at screening visit:  
• 
Clinical history and physical exam (per standard of care) 
• 
Informed consent obtained and documented 
• 
Review of eligibility criteria 
• 
Pre-treatment biopsy 
• 
Screening assessments (see schedule of events in section 7.13) 
 
Toxicities that occur prior to the start of treatment will not be subject to analysis.  Demographic 
information, informed consent, and inclusion/exclusion information are the only data required for 
individuals who are screen failures. 
 
 
BASELINE ASSESSMENTS 
 
Baseline assessments should occur prior to the start of olaparib on Day 1 of Cycle 1.  
Participants will be evaluated for medical history, physical examination, vital signs, performance 
status, concomitant medications, blood sampling for hematology and laboratory tests, and any 
other specific assessments listed in Section 7.14, Schedule of Events.  
 
 
ASSESSMENTS DURING TREATMENT 
 
Procedures to be conducted during the treatment phase of the study are presented in the 
Schedule of Events (Section 7.13). Visits should occur on Day 1 of every cycle.  Under certain 
circumstances (e.g., clinic holiday, inclement weather) scheduled visits may be delayed by no 
more than 3 days, or may occur earlier than scheduled by no more than 3 days during each 
treatment cycle cycles. Screening procedures performed within 72 hours of Cycle 1 Day 1 
(C1D1) do not need to be repeated on C1D1. 

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EARLY TERMINATION OR END OF TREATMENT VISIT 
 
Any participant that completes or discontinues treatment must be evaluated within 30 (+7) days 
after termination or prior to the initiation of any other off-study interventional therapy, if not 
performed within the last 30 days.  End of treatment assessments are listed in Section 7.14, 
Schedule of Events.   
 
 
FOLLOW-UP 
 
Participants will be followed every 6 months (± 14 days) after removal from protocol therapy for 
a maximum of 1 year post-treatment.  At a minimum, participants will be followed-up for disease 
status and survival.  This information may be updated periodically via electronic health records, 
or follow-up contact may be made with the participant (by phone) or their treating physician to 
that end.  Any follow-up visits will be consistent with standard of care, and assessments are 
listed in Section 7.14.  Participants removed from protocol therapy for unacceptable AE(s) will 
be followed until resolution or stabilization of the AE.   
 
A participant that discontinues the on-study assigned therapy due to progression, refusal, 
intolerable toxicity, desire for alternative non-protocol therapy, or other trials will be followed for 
disease and survival status. 
 
 
UNSCHEDULED VISITS 
 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed (e.g., laboratory or clinical assessments) at those visits should be recorded in the 
eCRF. 
 

 
126 
 
 
SCHEDULE OF EVENTS 
 
Table 33. Study Dosing Schedule 
Study agent 
Cycle 1 
Cycle 2+ (Days) 
 
 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
OlaparibA 
Days 1-28 
X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DurvalumabB 
- 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SelumetinibC 
- 
X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CapivasertibD 
- 
X X X X  
 
 X X X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
CeralasertibE 
- 
X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Olaparib is administered at a continuous dose of 300 mg PO BID for all 28 days of the treatment cycle (i.e., D1-28).  For Cycle 2 onwards, 
olaparib is only administed to participants assigned to Arms 1, 2, and 3.  
B Durvalumab (Arm 1 only) is administered as a 1500 mg IV infusion (every 4 weeks), on Day 1 of each cycle.  
C Selumetinib (Arm 2 only) is administered at a continuous dose of 75 mg PO BID for all 28 days of the treatment cycle.   
D Capivasertib (Arm 3 only) is administered at a dose 400 mg PO BID for 4 days with intermittent 3-day breaks in treatment  
E Ceralasertib (Arm 4 only) is administered at a dose of 240 mg PO BID on Days 1 to 14 of each cycle. 
 
Table 34. Planned study assessments 
Visit Days 
(± 3 Days)* 
Screening 
Cycle 1 
Cycle 2 
Cycle 3-13 
End of 
Treatment† 
Follow-up‡ 
Days -28 to -1 Day (D) 1** 
D15 
D1 
D8§ D15 
D1 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant medicationsA 
X 
X 
X 
X 
 
X 
X 
X 
 
Physical ExaminationB 
X 
X 
X 
X 
 
X 
X 
X 
X 
HematologyC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BiochemistryC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Glucose (fasting)Arm 3 only) 
X 
X 
X 
X 
 
 
X 
X 
X 
Cholestrol (fasting)Arm 3 only 
X 
X 
Every 12 weeks, or as clinically indicated  
X 
X 
Tumor Markers  
X 
X 
 
X 
 
X 
X 
X 
 

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Table 34. Planned study assessments 
Visit Days 
(± 3 Days)* 
Screening 
Cycle 1 
Cycle 2 
Cycle 3-13 
End of 
Treatment† 
Follow-up‡ 
Days -28 to -1 Day (D) 1** 
D15 
D1 
D8§ D15 
D1 
 
 
(CEA, CA 15-3, CA 27-29) 
TSH 
X 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
XArm 3 only  
X 
X 
 
 
X 
XArm 3 only 
XArm 3 only 
ECGArm 1, Arm 2, Arm 4 
X 
As clinically indicated – Refer to Section 7.1.5 
 
 
ECGArm 3 only 
X 
X 
 
X 
 
 
ECG on Cycle 3 D1 – 
thereafter every 12 
weeks or more 
frequent if clinically 
indicated 
 
 
MUGA/ECHOD 
X 
Arm 1, 3, and 4 – only as clinically indicated 
Arm 2 (selumetinib) – every 3 months while receiving selumetinib 
 
 
Pregnancy testE 
X 
 
X 
X 
 
 
X 
 
 
Medical Diary 
 
X 
 
X 
 
 
X 
 
 
Mediport placementF 
X 
 
 
 
 
 
 
 
 
 
RadiologyG 
X 
 
 
 
 
 
X♦ 
X 
X♦♦ 
 
AE assessmentH 
X 
Continuously monitored 
X 
 
Fecal sample collectionI 
X 
 
X 
X 
 
 
 
X 
 
Tumor tissue biopsyJ 
X 
 
X∆ 
 
 
 
 
 
X 
Research blood samplesK 
X 
X 
X 
X 
 
 
XK 
X● 
 
QOL AssessmentsL 
X 
 
 
At end of every 2nd treatment cycle 
X 
 
Survival Outcomes 
 
X 
X 
X 
 
X 
X 
X 
X 
 
* Ideally, the clinic visit and all the study requirements should be performed on Day 1 of each cycle, but may be performed within 3 days before or after that day.  
** Baseline visit should be conducted on Cycle 1 Day 1 prior to initiating study therapy, but may occur up to 3 days earlier. 
† Participants deriving clinical benefit may, at the investigator's discretion, continue therapy.  

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Table 34. Planned study assessments 
Visit Days 
(± 3 Days)* 
Screening 
Cycle 1 
Cycle 2 
Cycle 3-13 
End of 
Treatment† 
Follow-up‡ 
Days -28 to -1 Day (D) 1** 
D15 
D1 
D8§ D15 
D1 
 
 
‡ Participants will be followed for up to 1 year post-treatment. Participants may be contacted by phone, and survival status will be collected and documented. 
Hematology and Biochemistry should be collected 30 days post last dose of study agent.  
§ A visit on Day 8 during Cycle 2 is only required for participants receiving ceralasertib. Only hematology and biochemistry assessments are required at these visits. 
For participants receiving ceralasertib in Cycles 3 and subsequent treatment cycles, if thrombocytopenia is observed, then hematology and biochemistry assessments 
are required on Days 8 and 15 of each cycle. 
A For concomitant medications – enter new medications started during the trial through the end of treatment visit. 
B All physical exams will include assessing weight, vital signs, and ECOG performance status. Height will be collected at screening only.   
C Hematology and biochemistry tests should be collected pre-dose on Day 1 of every 28-day cycle. Testing for HIV, HCV B, or C will only take place during screening.  
D A baseline MUGA/ECHO should be performed at screening for all participants, and thereafter only as clinically indicated for Arms 1 and 4. For Arm 2 (selumetinib) 
only – a baseline ECHO is required is required prior to initiating selumetinib. Thereafter, an ECHO shoud be performed every 3 months while receiving selumetinib. 
For Arm 3 (capivasertib), only as clinically indicated. 
E For women of reproductive potential, a serum (preferred) or urine pregnancy test should be performed within 14 days prior to the first dose of trial treatment. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Pregnancy tests (serum 
and/or urine tests) should be repeated, if required, per institutional guidelines. 
FMediport placement is at the discretion of the investigator, and is to be installed at any time. 
G Radiographic imaging will be conducted according to standard of care and follow institutional guidelines. Imaging modalities may include, but are not limited to, CT 
and/or MRI.  The initial tumor imaging at screening will be performed within 28 days prior to the first dose of trial treatment.  Scans performed as part of routine clinical 
management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. 
Measurable disease based on RECIST 1.1 must be confirmed by the investigator and/or radiologist. 
H AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.  Record grade 3 and 4 AEs occurring within 30 days after the last dose of trial treatment. Report grade 3 and 4 hem and non-hem SAEs (related and 
unrelated to trial treatment) occurring up until 90 days after the last dose of trial treatment, or the start of new anti-cancer treatment, whichever comes first. Afterward, 
report only SAEs that are related to trial treatment. 
I This is an optional procedure, and participants' refusal will not impact their continued trial eligibility.   
J  Pre-treatment core biopsies are required prior to the initiation of protocol therapy. Samples obtained at the time of diagnosis before registration to this study may be 
submitted if they were collected within 3 months prior to the start planned study treatment. An additional, optional, tissue biopsy may be collected at time of disease 
progression. 
K Research blood draws should be performed at time of pre-treatment Biopsy (if fresh tissue is collected), C1D1 (Baseline), C1D15, at time of on-treatment biopsy, 
C2D1, C3D1, C4D1, C6D1, End of Treatment visit, and at the time of the optional disease progression biopsy (if it occurs).  Please refer to SMMART-AMTEC 
Laboratory Manual for additional details. For participants receiving durvalumab, research blood draws should occur prior to initiation of durvalumab infusion. On day-
of-biopsy collections, it is highly preferred to collect research blood prior to tissue collection. 
L QOL surveys (QLQBR23, QLQC30) will be collected at baseline, after completion of every two cycles of therapy and upon study completion or early termination.   
♦ On-study radiographic imaging will follow standard of care and should occur every 2 months, or as clinically indicated. 
♦♦ Post-treatment follow-up imaging will follow standard of care.  
∆The on-study tumor collection should occur after 2-weeks of starting olaparib monotherapy (i.e., Cycle 1  Day 14 [± 7]) days. 
● Research blood collection may continue after completion of on-study treatment and will coincide with standard of care visits. 

 
129 
 
8. EFFICACY MEASURES 
 
Tumor response will be determined per the investigators’ assessment, according to RECIST 
v1.1 183, and will be adapted using irRECIST184 when evaluating disease progression to account 
for the unique tumor response characteristics associated with immunotherapy (i.e., Arm 1 only).  
 
 
DEFINITION OF EFFICACY MEASURES 
 
8.1.1 DISEASE PARAMETERS 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as > 20 mm by chest x-ray or as > 
10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same participant, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition, should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.  
 
Non-target lesions. All other lesions (or sites of disease), including any measurable lesions over 
and above the 5 target lesions, should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-

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up.  
 
 
DISEASE EVALUATION 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. Use of MRI is also acceptable.   
 
FDG-PET: Use of FDG-PET scanning to complement CT scanning may be utilized in the 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-
up CT  scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
Cytology, Histology: Cytologic and histologic techniques can be used to differentiate between 
PR and CR in rare cases.   
 
Tumor markers: Tumor markers (Section 7.3.3) alone cannot be used to assess response. This 
data will be collected but will not be used for the purpose of response evaluation. 
 
 
EFFICACY CRITERIA FOR TUMOR RESPONSE 
 
8.3.1 EVALUATION OF TARGET LESION 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 

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Partial Response (Pr): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for Pr nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
8.3.2 EVALUATION OF NON-TARGET LESION 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal 
limit, they must normalize for a participant to be considered in 
complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a 
single lesion increase.    
 
Although a clear progression of non-target lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed 
at a later time by the principal investigator. 
 
8.3.2.1 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e., not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical location that was not scanned 
at baseline is considered new and will indicate PD.  If a new lesion is equivocal (because of 
small size etc.), follow-up evaluation will clarify if it truly represents new disease and if PD is 
confirmed, progression should be declared using the date of the initial scan on which the lesion 
was discovered 
 
8.3.3 OBJECTIVE RESPONSE RATE 
 
The ORR is the proportion of participants that achieve a best overall CR or Pr (per RECIST v1.1 

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criteria).  The best overall tumor response is assessed from the start of the combination study 
intervention until discontinuation of protocol-directed therapy (i.e., EOT).  In cases of disease 
progression, the smallest measurements recorded since the start of treatment should be used 
as the reference.  The best overall response for each participant evaluated during the course of 
this study depends on the findings of both target and non-target lesions, and also includes the 
occurrence of any new lesion (Table 35). Below is the summary table of overall response at a 
certain time point per RECIST guidelines. 
 
 
8.3.4 CLINICAL BENEFIT RATE 
 
CBR is defined as the percentage of participants who have achieved complete response, partial 
response, and stable disease (i.e., CR + Pr + SD) for at least 6 months on study treatment.  
 
8.3.5 DURATION OF RESPONSE 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or Pr (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented taking as reference for progressive 
disease the smallest measurements recorded since the treatment started.  The duration of 
overall CR is measured from the time measurement criteria are first met for CR until the first 
date that progressive disease is objectively documented.  If a participant dies, irrespective of 
cause, without documentation of recurrent or progressive disease beforehand, then the date of 
death will be used to denote the response end date. 
 
Duration of stable disease:  Stable disease is measured from the time of having completed at 
least one cycle of olaparib monotherapy until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
8.3.6 PROGRESSION-FREE SURVIVAL 
 
PFS is defined as the time after having completed at least one cycle of olaparib monotherapy to 
Table 35. Best Overall Response: Participants with target ± non-target disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Best Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD or NE 
No 
Pr 
CR 
Not evaluated 
No 
Pr 
Pr 
Non-CR/non-PD or NE 
No 
Pr 
SD 
Non-CR/non-PD or NE 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression 
 
Note: Subjects with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after discontinuation of treatment 

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the first of either recurrence or relapse (anywhere in the body) or death at the time of last follow-
up at 12-months. 
 
8.3.7 OVERALL SURVIVAL  
 
OS is defined as the time after having completed at least one cycle of olaparib monotherapy up 
to 6 months following the completion of on-study treatment to the date of death or last follow-up 
at 12 months. 
 
 
RESPONSE REVIEW 
 
Response assessment will be determined by the principal investigator. 
 
 
DEFINITION OF TUMOR RESPONSE USING IMMUNE RELATED RESPONSE 
CRITERIA (irRC) 
 
RECIST v1.1 criteria will be adapted to account for the unique tumor response characteristics 
associated with immunotherapy treatments such as durvalumab and will be used for sensitivity 
analysis (i.e., those assigned to Arm 1).  Immunotherapeutic agents such as durvalumab may 
produce anti-tumor effects by potentiating endogenous cancer-specific immune responses.  The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Thus, standard RECIST 1.1 
may not provide an accurate response assessment of immunotherapeutic agents such as 
durvalumab.   
 
irRECIST is identical to RECIST 1.1, but adapted to account for the unique tumor response 
seen with immunotherapeutics (e.g., durvalumab).184  The assessment of unidimensional target 
lesions and response categories per irRC are identical to RECIST 1.1.  Summary of 
measurements is as follows: 
 
Measurable lesions: ≥10 mm in the longest diameter (5 lesions total, 2 per organ) 
Measurement of each lesion: The longest diameter (cm) 
Sum of the measurements: The sum of the longest diameters of all target lesions and new 
lesions (if any) 
 
8.5.1 DEFINITION OF INDEX LESION RESPONSE USING IRRECIST 
 
Complete Response (CR): Complete disappearance of all target and non-target lesions; Nodal 
short axis diameter <10 mm; No new lesions. 
 
Partial Response (PR): Decrease, relative to baseline, of 30% in tumor burden relative to 
baseline; Non-unequivocal progression of non-target lesions; No new lesions.  
 
Stable Disease (SD): Does not meet criteria for either CR or PR, in the absence of progressive 
disease. 
 
irProgressive Disease (irPD): At least 20% (minimum 5 mm) increase in total measured tumor 
burden when compared with nadir or progression of non-target lesions or new lesions.  
Confirmation of progression requires two (2) consecutive observations at a minimum 4 weeks 

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(and maximum of 12 weeks) after the first irPD assessment.  Where confirmed irPD includes 
new unequivocal progression or worsened progression from initial PD visit; appearance of 
another new lesion.  
 
8.5.2 IMPACT OF NEW LESIONS ON IRRECIST 
 
The presence of new lesion(s) does not define progression. The measurements of the new 
lesion(s) are included in the sum of the measurements. 
 

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9. SAFETY 
 
 
SPECIFICATION OF SAFETY PARAMETERS 
 
The investigator is responsible for monitoring the safety of participants who have enrolled in the 
study. The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. Safety assessments will be based on medical review of 
adverse events and the results of safety evaluations at specified time points, as described in 
Section 7.14, Schedule of Events. The investigator will follow any clinically significant adverse 
events persisting at the end of treatment visit until resolution/stabilization or death, whichever 
comes first. 
 
 
DEFINITIONS 
 
9.2.1 ADVERSE EVENT (AE) 
 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) 
E6(R1) defines an AE as: 
 
Any untoward medical occurrence in a patient or clinical investigation participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
An AE includes but is not limited to any clinically significant worsening of a participant’s pre-
existing condition. An abnormal laboratory finding (including ECG finding) that requires an 
action or intervention by the investigator, or a finding judged by the investigator to represent a 
change beyond the range of normal physiologic fluctuation, should be reported as an AE. 
 
Adverse events may be treatment-emergent (i.e., occurring after initial receipt of investigational 
product) or non-treatment emergent. A non-treatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the participant has received investigational product.  
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
participant being enrolled in the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or non-serious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
 
The term AE is used to include both serious and non-serious AEs. 
 
9.2.2 SERIOUS ADVERSE EVENT (SAE) 
 
An SAE is an AE occurring during any study phase (i.e., screening, run-in, treatment, wash-out, 
follow-up), at any dose of the study drugs that fulfills one or more of the following criteria: 
 
• 
Death,  
• 
A life-threatening adverse event,  

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• 
In-patient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and/or participant may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include: 
 
• 
Allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
• 
Blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 
• 
The development of drug dependency or drug abuse.  
 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 
 
9.2.2.1 
New Malignancies On-study 
 
AEs for malignant tumours reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a Non-
Serious AE. For example, if the tumour is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfill the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
 
9.2.3 UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers UPs involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
2. Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
This study will use the OHRP definition of UP. 
 
9.2.4 SEVERITY OF EVENT 
 
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the event of an AE for which no grading scale exists, the Investigator will classify the AE as 
defined below:  
 
• Mild (grade 1) – An event that is usually transient in nature and generally not interfering with 
normal activities 
• Moderate (grade 2) – An event that is sufficiently discomforting to interfere with normal 
activities 
• Severe (grade 3) – An event that is incapacitating with inability to work or do usual activity, 
or inability to work or perform normal daily activity 
• Life-threatening/debilitating (grade 4) – An event that puts the participant at immediate or 
potential risk of death, requires hospitalization, or which drastically impacts a participant’s 
well-being 
• Fatal (grade 5) 
 
9.2.5 ASSESSMENT OF CAUSALITY RELATIONSHIP TO STUDY AGENT  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
• Definite – The AE is clearly related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unrelated –The AE is clearly NOT related to the study treatment. 
 
 
EXPECTEDNESS 
 
The investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. 
 
 
ADVERSE EVENT LIST(S)  
 
9.4.1 ADVERSE EVENT LIST FOR OLAPARIB 
 
Refer to the current version of the Olaparib investigator brochure insert regarding detailed risks 
and expected AEs of olaparib.  In brief, common AEs associated with olaparib include: rash 
(10% to less than 20%), constipation (22% ), decrease in appetite (21% to 22% ), diarrhea (21% 
to 33% ), indigestion (up to 25% ), nausea (58% to 76%), anemia, (all grades [23% to 44%]), 
leukopenia, (all grades [25%]), neutropenia (all grades [27%]), nasopharyngitis (up to 43%), 
respiratory tract infection (22% to 27% ), and fatigue (46%).  Serious AEs reported include: 
anemia (grade 3 or 4 [4% to 20%]), myeloid leukemia (Up to 2%), and pneumonitis (< 1%).  
 
9.4.1.1 
Olaparib Adverse Events of Special Interest (AESI) 
 
AESIs are events of scientific and medical interest specific to the further understanding of 
olaparib’s safety profile and require close monitoring and rapid communication by the 
investigators to AstraZeneca. AESI for olaparib are the Important Identified Risk of MDS/AML 
and Important Potential Risks of  new primary malignancy (other than MDS/AML), and 
pneumonitis.   
 
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event.  During the study, there may be other events identified as 

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AESIs that require the use of a questionnaire to help characterize the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
 
9.4.2 ADVERSE EVENT LIST FOR DURVALUMAB 
 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus and 
diabetes insipidus, hypophysitis/hyperpituiarism, and adrenal insufficiency) hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, 
rash/pruritus/dermatitis (including pemphigoid), myocarditis, myositis/polymyositis, immune 
thrombocytopenia, infusion related reactions, hypersensitivity reactions, pancreatitis, serious 
infections, and other rare or less frequent inflammatory events including neuromuscular toxicities 
(eg, Guillain-Barré syndrome, myasthenia gravis). 
 
For information on all identified and potential risks with durvalumab, please always refer to the 
current version of the durvalumab IB. 
 
Further information on these risks can be found in the current version of the durvalumab IB. 
In monotherapy, clinical studies AEs (all grades) reported very commonly (≥ 10% of patients) are 
fatigue, and decreased appetite. Approximately 10% of patients experienced an AE that resulted 
in permanent discontinuation of durvalumab. 
 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicities (refer to separate durvalumab TMG).  
 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB. 
 
9.4.2.1 
Durvalumab Adverse Events of Special Interest 
 
AESIs observed with durvalumab include: 
 
• 
Diarrhea / Colitis and intestinal perforation 
• 
Pneumonitis / ILD 
• 
hepatitis/transaminase increases 
• 
Endocrinopathies (i.e., events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- 
and hypothyroidism and type I diabetes mellitus) 
• 
Rash / Dermatitis 
• 
Nephritis / Blood creatinine increases 
• 
Pancreatitis/serum lipase and amylase increases   
• 
Myocarditis 
• 
Myositis / Polymyositis 
• 
Neuropathy / neuromuscular toxicity (e.g., Guillain-Barré, and myasthenia gravis) 

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• 
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, hematological and rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
 
Further information on these risks (e.g., presenting symptoms) can be found in the current version 
of the durvalumab Investigator’s Brochure. More specific guidelines for their evaluation and 
treatment are described in detail in the separate Dosing Modification and Toxicity Management 
Guidelines.  These guidelines have been prepared by AZ to assist the Investigator in the exercise 
of his/her clinical judgment in treating these types of toxicities.  These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting investigator. 
 
9.4.3 ADVERSE EVENTS LIST FOR CAPIVASERTIB 
 
For information on all identified and potential risks with capivasertib please refer to the current 
version of the capivasertib IB.  AEs observed with capivasertib (irrespective of causality) , 
include: diarrhea nausea vomitingstomatitisrashdry skinpuritishyperglycemiadecrease appetite 
and drug hypersensitivity  
 
9.4.3.1 
Capivasertib Adverse Events of Special Interest 
 
Adverse events of special interest to be observed with capivasertib include: 
 
• 
Hyperglycaemia 
• 
Non-infectious diarrhea 
• 
Pneumonia 
• 
Rash 
• 
Stomatitis 
• 
Torsade de pointes/QT Prolongation 
 
9.4.4 ADVERSE EVENTS LIST FOR SELUMETINIB 
 
For information on all identified and potential risks with selumetinib please always refer to the 
current version of the selumetinib IB.  In pooled data of monotherapy clinical studies (n = 347) 
selumetinib dosing, the observed AEs, irrespective of causality, include: dry skin (all grade, 
57.2%), hair changes (all grade 6.1%), paronychia (all grade 2.6%), rashes (acneiform; all grade 
49.6%; grade ≥ 3, 8.1%), and rashes (all grades, 67.7%, grade ≥3 10.4%), diarrhea (all grade, 
48.1%; grade ≥ 3, 2.3%), nausea (all grade, 36.6%; grade ≥3, 1.7%, vomiting (all grade, 23.6%; 
grade ≥3, 2.3%), stomatitis (oral mucositis, all grade, 8.1%), dry mouth (all grade, 6.6%), asthenic 
events (all grade, 34.9%, grade ≥3, 5.8%), peripheral edema (all grade, 31.1%; grade ≥3, 1.2%), 
facial edema (all grade, 11.2%), pyrexia (all grade, 8.9%; grade ≥3, 0.9%), dyspnea (all grade, 
16.4%; grade ≥3, 2.9%), vision blurred (all grade, 6.1%).   
 
Kurnit et al114 has preliminarily investigated the combination of olaparib and selumetinib.  In early 
findings of 14 patients that received the treatment combination, the authors reported anemia and 
hypophosphatemia (any grade) as the most common AEs (additional AEs are described in Table 
36) 

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Table 36. Kurnit et al., AEs reported with olaparib and selumetinib combination 
Adverse Event 
Any Grade 
Grade 3 
Anemia 
79% 
  
Hypophosphatemia 
79% 
  
Acneiform Rash 
71% 
7% 
Fatigue 
64% 
7% 
Nausea 
57% 
  
Diarrhea 
50% 
  
Elevated aspartate aminotransferase 
50% 
7% 
Oral mucositis 
50% 
  
Dry mouth 
43% 
  
Decreased white blood cell count 
36% 
7% 
Dysgeusia 
36% 
  
Elevated CPK 
36% 
7% 
Other skin effects 
36% 
  
Anorexia 
29% 
  
Constipation 
29% 
  
Dizziness 
29% 
  
Dry skin 
29% 
  
Edema 
29% 
  
Elevated creatinine 
29% 
  
Neutropenia 
21% 
7% 
Decreased ejection fraction 
14% 
7% 
Abdominal pain 
7% 
7% 
Elevated bilirubin 
7% 
7% 
Hepatic pain 
7% 
7% 
Thromboembolic event 
7% 
7% 
 
9.4.4.1 
Selumetinib Adverse Events of Special Interest 
 
Adverse events of special interest to be observed with selumetinib include: 
 
• 
Ocular toxicity (Chorioretinopathy (central serous retinopathy [CSR]), Retinal 
detachment, Retinal tear, Vision blurred, Visual impairment, Vitreous floaters, Photopsia, 
Eye disorder, Photophobia, Retinal vein occlusion (RVO), Detachment of retinal pigment 
epithelium (Retinal pigment epithelial detachment [RPED]).  
• 
Hepatotoxicity (Drug-induced liver injury, ALT increased, AST increased) 
• 
Muscular toxicity (Blood creatine phosphokinase increased, Musculoskeletal pain, 
Muscular weakness, Myalgia, Rhabdomyolysis, Myoglobin blood increased, Myoglobin 

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urine present, Acute kidney injury, Myopathy)  
• 
Cardiac toxicity (Ejection fraction decreased, edema peripheral, Peripheral swelling, 
Oedema, Left ventricular dysfunction, Ventricular dysfunction) 
 
9.4.5 ADVERSE EVENTS LIST FOR CERALASERTIB 
 
For information on all identified and potential risks with ceralasertib please always refer to the 
current version of the ceralasertib IB. The most common AEs (i.e., >15%) reported among 
patients with solid tumors receiving ceralasertib monotherapy includes: gastrointestinal 
disorders (61.5%). fatigue (38.5%), anemia (38.5%), musculoskeletal and connective tissue 
disorders (46.2%), infections and infestations (30.8%), respiratory, thoracic and mediastinal 
disorders (30.8%), and nervous system disorders (23.1%).  
 
 
ADVERSE EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of a UP, AE, or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs, including local and systemic reactions not meeting the criteria for SAEs, 
will be captured on the appropriate eCRF.   
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
The maximum CTCAE grade reported 
• 
Changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IPs (definite, probable, unrelated) 
• 
Action taken with regard to IPs 
• 
Administration of treatment for the AE 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date the AE met criteria for SAE 
• 
Date the Investigator became aware of the SAE 
• 
Seriousness criteria fulfilled 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether an autopsy was performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment in relation to other medication, as explained in Section  9.2.5 
• 
Description of the SAE 
 
All AEs occurring while on study must be documented appropriately regardless of relationship. 
All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  

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Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization.  
The Investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 days for AEs, and for SAEs, up to 30 days (for Arms 2, 3, 
and 4) or 90 days (for Arm 1) after the last dose of study drug or until the initiation of alternative 
anticancer therapy, whichever occurs first. Any SAE that occurs after treatment with alternative 
therapy will be reported only if the investigator or current treating physician has assessed the 
SAE as related to the study treatment. Adverse events will be evaluated using the CTCAE v5.0. 
  
9.5.1 ADVERSE EVENTS AFTER THE 90 DAY FOLLOW-UP PERIOD 
 
All SAEs will be reported, whether or not considered causally related to the investigational 
product or the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last dose 
of study drug or until the initiation of alternative anticancer therapy. The investigator and/or AZ 
are responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE 
as per local requirements. 
 
For Pharmacovigilance purposes and characterization, any SAE of MDS/AML or new primary 
malignancy occurring after the 30-day follow-up period for olaparib, capivasertib, selumetinib, 
and ceralasertib, and 90-day follow-up period for durvalumab, should be reported to 
AstraZeneca Patient Safety regardless of investigator’s assessment of causality or knowledge 
of the treatment arm.  Investigators will be asked during the regular follow-up for overall survival 
if the participant has developed MDS/AML or a new primary malignancy and prompted to report 
any such cases.   
 
At any time after a participant has completed the study, if an investigator learns of any SAE, 
including sudden death of unknown cause, and he/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator should 
notify AstraZeneca, Patient Safety. 
 
If participants who are gaining clinical benefit are allowed to continue study treatment post data 
cut off and/or post-study completion, then all SAEs must continue to be collected and reported 
to Patient Safety within the usual timeframe. 
 
Otherwise, after study treatment completion (i.e., after any scheduled post-treatment follow-up 
period has ended), there is no obligation to actively report information on new AEs or SAEs 
occurring in former study participants. This includes new AEs/SAEs in participants still being 
followed up for survival but who have completed the post-treatment follow-up period (30 days). 
 
 
OVERDOSE 
 
9.6.1 OLAPARIB, SELUMETINIB, CAPIVASERTIB, AND CERALASERTIB  
 
There is currently no specific treatment in the event of an overdose with olaparib, selumetinib, 

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capivasertib, and ceralasertib, and possible symptoms of overdose are not established. Each 
study agent must only be used in accordance with the dosing recommendations in this protocol.  
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose. The Maximum Allowed  Dose for each agent is as follows:  
 
• 
Olaparib – 300 mg twice daily (tablet). 
• 
Selumetinib – 75 mg twice daily (capsule)  
• 
Capivasertib – 400 mg twice daily (tablet) 4 days on / 3 days off 
• 
Ceralasertib – 240 mg twice daily (tablet) 
 
Adverse reactions associated with an overdose should be treated symptomatically and should 
be managed appropriately. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 9.7. 
For other overdoses, reporting must occur within 30 days. 
9.6.2 DURVALUMAB 
 
An overdose is defined as a patient receiving a dose of durvalumab in excess of that specified 
in the Investigator’s Brochure unless otherwise specified in this protocol. 
 
Any overdose of a study participant with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee. If the overdose results in an AE (see 
Section 9.2.1), the AE must also be recorded as an AE. Overdose does not automatically make 
an AE serious, but if the consequences of the overdose are serious, for example, death or 
hospitalization, the event is serious and must be recorded and reported as an SAE (see Section 
9.2.2). There is currently no specific treatment in the event of an overdose of durvalumab.  
 
The investigator will use clinical judgment to treat any overdose. 
 
 
REPORTING PROCEDURES 
 
9.7.1 OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
 
Unanticipated Problems and AEs will be reported to OHSU IRB according to the policies, 
procedures, and guidelines posted on the OHSU IRB web site. 
 
Events that must be reported by the Investigator to the IRB are detailed in the OHSU IRB 
Investigator Guidance: Prompt Reporting Requirements (HRP-801). At a minimum, events 
requiring reporting to the IRB include: 
• 
Any new or increased risk related to the research, including AEs or IND safety reports 

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that require a change to the protocol or consent,  
• 
New FDA black box warning,  
• 
Publications identifying new risks,  
• 
Data Safety Monitoring Board/Committee letters recommending changes or discussing 
new risks 
• 
Unanticipated adverse device effect 
• 
Unauthorized disclosure of confidential participant information 
 
9.7.2 MEDWATCH REPORTING  
 
The Sponsor-investigator is required (per 21 CFR 312.32) to report AEs that meet certain 
criteria to the FDA through the MedWatch reporting program, even if the trial involves a 
commercially available agent. Adverse events to be reported include any UPs (i.e., not listed in 
the package insert) and any SAEs with a suspected association to the investigational product. 
 
Adverse events that occur during clinical studies are to be reported to FDA as specified in the 
investigational new drug/biologic regulations using Form FDA 3500A, the Mandatory Reporting 
form (available here). A copy of Form FDA 3500A and supporting materials will be kept on file in 
the study regulatory binder.  
 
The Sponsor-investigator will concurrently forward all such reports to AstraZeneca. A copy of 
the MedWatch/AdEERs report must be emailed to AstraZeneca at the time the event is reported 
to the FDA.  It is the responsibility of the sponsor to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting requirement timelines and 
to ensure that these reports are also submitted to AstraZeneca at the same time. 
 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
• 
“Notification from an Investigator Sponsored Study” 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-18-13868)  
 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events 
in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com  
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA. 
 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca, preferably using the MedDRA coding language for serious adverse 
events. This information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly.  
 
9.7.3 REPORTING OF PREGNANCY 
 

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To ensure participant safety, each pregnancy in a participant on study treatment must be 
reported within 24 hours of learning of its occurrence.  The pregnancy should be followed to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or any pregnancy- or 
childbirth-related and/or newborn complications. 
 
The pregnancy should be recorded on the pertinent eCRF and reported by the Investigator to 
the IRB. Pregnancy follow-up should be reported using the same form.  Any SAE experienced 
during pregnancy must be reported. 
  
If, while on study treatment, a participant’s sexual partner becomes pregnant, the pregnancy 
and pregnancy outcomes must also be reported as described above.  Consent to report 
information regarding the pregnancy should be obtained from the pregnant individual. 
 
 
REPORTING OF DEATHS TO ASTRAZENECA 
 
All deaths that occur during the study, or within the protocol-defined 30 days post-last dose of 
selumetinib, capivasertib, or ceralasertib (Arms 2, 3, and 4), or 90 days post-last dose of 
durvalumab (Arm 1) safety follow-up period must be reported to AstraZeneca as follows: 
• 
Death that is clearly the result of disease progression should be documented but should not 
be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to AstraZeneca as an SAE within 24 hours. The 
report should contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death.  
• 
Deaths with an unknown cause should always be reported as an SAE.  
 
Deaths that occur following the protocol-defined 30-day post-last dose of selumetinib, 
capivasertib, or ceralasertib, or 90-day post-last-dose of durvalumab, safety follow-up period will 
be documented as events for survival analysis, but will not be reported as an SAE. However, if 
an investigator learns of any SAEs, including death, at any time after the participant has been 
permanently withdrawn from the study, and he/she considers there is a reasonable possibility 
that the event is related to study treatment, the investigator should notify the study sponsor and 
AstraZeneca/MedImmune Drug Safety. 
 
 
STUDY STOPPING RULES 
 
The overall study will be paused, and appropriate authorities (e.g., IRB, Knight Data and Safety 
Monitoring Committee) notified if the following events occur: 
 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is unmanageable, or 
unexpected. 
• 
Death suspected to be related to the study intervention. 
• 
As indicated by statistical stopping rules in this protocol (Refer to Section 10.2.3.3). 
 

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10. STATISTICAL CONSIDERATIONS 
 
Refer to Section 3.1, Description of the Study Design for a detailed description of the study 
design and endpoints.  
 
 
ANALYSIS POPULATIONS  
 
The safety analysis set includes all enrolled participants that receive at least one dose of study 
medications.  
 
The efficacy analysis set includes all participants who receive at least one cycle of on-study 
treatment of olaparib in combination with durvalumab, selumetinib, capivasertib, or ceralasertib 
(based on treatment arm assignment), and have had their disease re-evaluated (i.e., at least 1-
post baseline disease assessment).  
 
 
DESCRIPTION OF STATISTICAL METHODS 
 
10.2.1 GENERAL APPROACH 
 
This is a multi-arm, open-label Phase II study to evaluate the efficacy of olaparib in combination 
with durvalumab, selumetinib, or capivasertib, or ceralasertib monotherapy to treat patients with 
metastatic TNBC.   
 
10.2.2 ANALYSIS OF PRIMARY ENDPOINT(S) 
 
Using the efficacy analysis set, the estimate of ORR will be measured independently for each 
treatment arm and reported with 95% exact confidence interval. Participants who, within their 
respective treatment arm, achieve a CR or a PR that is confirmed on a second scan at least 4 
weeks later on the current protocol will be qualified as achieving a response and will count 
towards the ORR measurement.  
 
10.2.3 ANALYSIS OF THE SECONDARY ENDPOINT(S)  
 
10.2.3.1 
Safety Endpoint  
 
The incidence of having Grade 3+ acute toxicity will be determined for participants with TNBC 
that received at least one dose of olaparib and/or durvalumab, selumetinib, capivasertib, or 
ceralasertib.  The 95% confidence interval will be reported with the point estimate of toxicity 
rate.  
 
10.2.3.2 
Efficacy Endpoints 
 
An estimate of CBR will be measured independently for each treatment arm and reported with 
95% exact confidence interval. Participants who, within their respective treatment arm, achieve 
a CR, PR, or SD for at least 6 months on the current protocol will be qualified as deriving benefit 
from therapy and will count towards the CBR measurement.  
 
The estimated distribution of the PFS, OS, and DOR for each treatment will be plotted using 
Kaplan Meier curves and reported with median survival and 95% confidence intervals if 
available. 
 

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10.2.3.3 
Interim Analysis and Stopping Rules – Arm 1 (olaparib and durvalumab) 
 
The trial will enroll 15 participants in stage 1. If 2 or less out of 15 respond, this treatment arm 
will be closed due to futility. Otherwise, the treatment arm will continue until a total of 28 
participants are enrolled. All participants enrolled in stage 1 (n=15) will need to complete at least 
1 post-baseline disease restaging assessment before the interim analysis can be completed.  
After 15 evaluable participants, recruitment to this treatment arm will be paused until the interim 
analysis is completed.  The proposed combination therapy for this treatment arm is considered 
promising and worth further investigation if there are 8 or more responses among 28 
participants.    
 
10.2.3.4 
Interim Analysis and Stopping Rules – Arm (olaparib in combination with selumetinib 
or capivasertib, or ceralasertib  monotherapy) 
 
Each treatment arm will independently enroll 11 participants in stage 1. If <2  of 11 respond in a 
given treatment arm, then that treatment arm will be closed due to futility. Within each treatment 
arm, if ≥2, but <5, of 11 participants respond, the respective treatment arm will continue until a 
total of 22 participants are enrolled to that arm.  For Arms 2-4, all participants enrolled in stage 1 
(n=11) will need to complete at least 1 post-baseline disease restaging assessment before the 
interim analysis can be completed.  After 11 evaluable participants, recruitment to that specific 
treatment arm will be paused until the interim analysis is completed.  The proposed combination 
therapy for treatment Arms 2 and-3 is considered promising and worth further investigation if 
there are 7 or more responses among 22 participants.  For Arms 2 and 3 only, if at the time of 
the stage 1 interim analysis, there are ≥ 5 of 11 responders within a given treatment arm, then 
an expansion cohort for TNBC patients without the biomarker characteristics will be opened 
using a Simon’ 2-stage design.   
 
10.2.3.5 
Biomarker Negative Expansion Cohort (Arms 2 and 3 only) 
 
Each biomarker negative expansion cohorts will only open after enrollment in Arm 2 or Arm 3, 
respectively, is completed. There is no formal plan to compare each treatment arm with its 
corresponding biomarker negative arm. 
 
Each biomarker negative treatment will independently enroll 9 participants in stage 1. If 1 or less 
of 9 participants responds, then the arm will be closed due to futility. If ≥2 of 9 participants 
respond, the the trial will continue on to stage 2 until a total of 19 participants are enrolled. The 
biomarker selection criteria for the respective arm will be considered unpromising if more than 5 
responses are observed in 19 participants.  
 
10.2.4 ANALYSIS OF EXPLORATORY ENDPOINTS 
 
As data warrant, exploratory analysis may be performed on each exploratory objective listed 
below: 
1. Examine response rates depending on tumor characteristics  
2. Identify predictive biomarkers of sensitivity to therapy  
3. Identify emerging mechanism of resistance to therapy tumor markers of emergence.  
4. Determine changes in tumor cells induced by PARP inhibitors 
5. Identify tumor markers suggestive of combinatorial therapy that could overcome 
resistance to therapy 
The results of these exploratory analyses may be reported separately from the clinical study 
report (CSR).  In general, descriptive statistics, histograms, and hierarchical clustering (e.g. 
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and to visualize cellular and molecular changes associated with study treatment.  For 
multiplexing IHC, statistically significant differences in unpaired and paired data will be 
determined using Kruskal-Wallis and Wilcoxon-signed rank tests.  False discovery rates will be 
estimated to control for multiple comparisons.  Where relevant, results from assays will be 
described by mean, standard deviation (SD), minimal, and maximal values.  Comparison of 
group variables may be assessed using nonparametric tests of independence (e.g., Chi-square 
test or Fisher’s exact test). 
 
10.2.4.1 
Analysis of Quality of Life Measures 
 
Patient reported QOL will be assessed by two standard questionnaires, one for all cancer 
patients (QLQC30) and one specific to breast cancer (QLQBR23).  Utility of QLQBR23 has 
been demonstrated in several breast cancer trials.175-177  In a longitudinal study, metastatic 
breast cancer patients, completion rates for both surveys administered seven times over a 24-
month period were >80%.178  QOL surveys will be collected at baseline, after completion of 
every two cycles of therapy and at study completion or early termination. 
 
QLQC30 is a 30-item measure and yields scores for 5 functional scales (physical, role, 
cognitive, social, and emotional), 3-symptom scales (nausea, pain, and fatigue), a global health 
and QOL scale, and perceived financial impact of treatment.179  QLQC30 can distinguish 
patients according to performance status and is the most commonly used QOL instrument in 
oncology research.180,181  Data from the EORTC QLQ-C30 instrument will be scored as 
previously described by Aaronson et al.185  
 
QLQBR23 is a 23-item instrument that measures symptoms and side effects related to 
treatment, body image, sexuality, and future perspective specific to breast cancer patients. 
QLQBR23 has high internal consistency (Cronbach’s a = 0.71-0.90), can distinguish between 
patients based on disease stage, performance status, treatment modality, or prior surgery, and 
is sensitive to change over time.182  The EORTC QLQ-BR23 data will be scored as described by 
the EORTC scoring manual.186 
 
The QOL measures will be summarized and presented over time graphically using box and 
spaghetti plots, in addition to summary tables.  Mixed effect model will be further used to 
analyze the longitudinal data.  For each instrument, the analysis will include all cycles for which 
at least 25% of participants in each arm that have an assessment. 
 
10.2.4.2 
Additional Analyses 
 
Additional analyses that may be performed after the completion of the end-of-study CSR will be 
documented in separate reports. These analyses may include but are not limited to the meta-
analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in a stand-alone analysis 
plan document. 
 
 
SAMPLE SIZE, POWER, ACCRUAL RATE, AND STUDY DURATION 
 
10.3.1 SAMPLE SIZE AND POWER 
 
10.3.1.1 
Arm 1 (olaparib and durvalumab) 
 

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A two-stage analysis will be performed using a Simon 2-stage Minimax design. The null 
(Immune checkpoint blockade alone) and alternative (Durvalumab and Olaparib) hypotheses 
are: H0: π = 0.15 and Ha: π = 0.35.  For the primary endpoint, a total sample size of 28 
participants will achieve 80 percent power to detect the overall response rate difference of 0.20 
using the two-stage Minimax design with one-sided type I error =0.05. The trial arm will be 
terminated in stage I if 2 or less out of the first 15 participants respond. If the trial goes on to 
stage 2, a total of 28 participants will be studied. If the total number responding is less than or 
equal to 7, the drug is rejected.  
 
10.3.1.2 
Arms 2-4 (olaparib and selumetinib, or capivasertib, or ceralasertib monotherapy) 
 
Fleming’s two-stage design will be used.187  The null (PARPi monotherapy) and alternative 
(olaparib and capivasertib, or selumetinib, or ceralasertib monotherapy) hypotheses are: H0: π = 
0.15 and Ha: π = 0.40 (refer to Section 3.1.1 for justification).  For the primary endpoint, a total 
sample size of 22 participants will achieve 80 percent power to detect the overall response rate 
difference of 0.25 with one-sided type I error=0.05.  In the first stage, 11 patients will be 
accrued.  If there are 1 or fewer responses in these 11 participants, the study arm will be 
terminated in stage 1.  Otherwise, 11 additional participants will be accrued for a total of 22.  
The null hypothesis will be rejected if 7 or more responses are observed in 22 participants. If 
there are 5 or more responses in 11 participants, the study will open expansion study with 
biomarker negative patients. 
 
For the biomarker negative expansion cohort (Arms 2 & 3 only): A two-stage analysis will be 
performed using a Simon 2-stage Minimax design. The null (PARPi monotherapy) and 
alternative hypotheses are: H0: π = 0.15 and Ha: π = 0.4 (refer to Section 3.1.1 for justification).  
For the primary endpoint, a total sample size of 19 participants will achieve 80 percent power to 
detect the overall response rate difference of 0.25 using the two-stage Minimax design with one-
sided type I error =0.05. The trial arm will be terminated in stage I if 1 or less out of the first 9 
participants respond. If the trial goes on to the stage 2, a total of 19 participants will be studied. 
The null hypothesis will be rejected if more than 5 responses are observed in 19 participants.  
 
 
HANDLING OF MISSING DATA 
 
Every attempt will be made to obtain data at the defined time points, as described in the primary 
and secondary endpoints. For time points that have no data, we will evaluate whether or not the 
other time points can be used to fulfill the primary and secondary data.  If the data are not 
sufficient to analyze specific endpoints, the participant’s data may be excluded entirely or 
partially, depending on the specific endpoints in question and in consultation with the 
biostatistician. No missing data will be imputed. Whenever possible, all available data will be 
included in the analysis. The sample size for each analysis will be clearly stated along with the 
reason for exclusion if any participant is excluded from the analysis due to missing data. 

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11. CLINICAL MONITORING 
 
 
OHSU KNIGHT CANCER INSTITUTE DATA & SAFETY MONITORING PLAN (DSMP) 
 
All clinical trials at the Knight are required to have a Data and Safety Monitoring Plan (DSMP). 
This study is under the oversight of the Knight Cancer Institute’s DSMC, as described in the 
Knight institutional DSMP. The Knight DSMP outlines the elements required to ensure the 
safety of clinical trial participants, the accuracy and integrity of the data, and the appropriate 
modification of cancer-related clinical trials for which significant benefits or risks have been 
discovered or when the clinical trial cannot be successfully concluded. The Knight DSMP also 
describes the methods and procedures for ensuring adequate oversight of cancer-related 
research at OHSU. 
 
As described in the Knight DSMP, regardless of a trial’s risk level and any specific Knight 
oversight in place, the Investigator is singularly responsible for overseeing every aspect of the 
design, conduct, and final analysis of his/her investigation. 
 
The OHSU Knight Cancer Institute’s DSMC will review and monitor toxicity and accrual data 
from this study.  The committee is composed of clinical specialists with experience in oncology 
and who have no direct relationship with the study. Information that raises any questions about 
participant safety will be addressed with the Investigator and study team. 
 
The Knight DSMC will review each protocol every 6 months, but may occur more often, if 
required, to review toxicity and accrual data (please refer to Knight DSMP for additional details 
on reporting and audit frequency). Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; all grade 2 or higher unexpected AEs 
that have been reported; summary of all deaths occurring within 30 days of study intervention, 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team.  Other information (e.g., 
scans, laboratory values) will be provided upon request.  
 
 
CLINICAL DATA & SAFETY MONITORING 
 
The OHSU Investigator is ultimately, singularly responsible for overseeing every aspect of the 
investigation, including design, governing conduct at all participating sites, and final analysis of 
study data.  
 
If monitoring is required, per the Knight DSMP, then monitoring visits will be performed during 
the study to ensure that the rights and well-being of human participants are protected, that the 
reported trial data are accurate, and that the conduct of the trial is in compliance with the 
protocol, GCP, and applicable regulatory requirements.  In this case, details of monitoring 
activities, including the designation of assigned monitoring entities, the scope of monitoring 
visits, timing, frequency, duration of visits, and visit reporting, will be included in a separate 
TSMP. 
 
In the absence of a formal monitoring plan, the Investigator may work with his/her study team to 
conduct and document internal monitoring of the study to verify the protection of human 
participants, quality of data, and/or ongoing compliance with the protocol and applicable 
regulatory requirements. 
 

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If, at any time, investigator noncompliance is discovered at participating sites, the investigator 
shall promptly either secure compliance or end the investigator’s participation in the study. 
 
Independent audits will be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
and that evidence of ongoing investigator oversight is present. 
 
 
QUALITY ASSURANCE & QUALITY CONTROL 
 
The investigational site will provide direct access to all trial-related source data/documents, and 
reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the Knight 
DSMC and/or regulatory authorities.  
 
All clinical trials at the Knight Cancer Institute are required to have a Data and Safety Monitoring 
Plan.  All clinical work conducted under this protocol is subject to ICH GCP guidelines.  This 
includes inspection of study-related records by the lead site, sponsor, its designee, or health 
authority representatives at any time. 
 
QA audit activities will occur as detailed in the Knight institutional DSMP.  All discrepancies, 
queries, deviations, observations, and findings of non-compliance will be compiled into a final 
audit report.  The PI must review and assess each finding, and generate a response to the audit 
report that incorporates a Corrective and Preventative Action (CAPA) plan.  The CAPA must 
analyze root cause(s) of noncompliance to determine the appropriate changes to correct and 
resolve issues and prevent a recurrence. 
 
Quality Control (QC) activities will occur to monitor and ensure the safety of study participants 
and the validity and integrity of data.  Monitoring will be a continuous, ongoing, and multifaceted 
process.  This includes review by the Knight DSMC and IRBs, as well as internal data quality 
control, review, and evaluation.  Site monitoring visits are central to this process and will include 
reporting to appropriate individuals with oversight responsibilities. 
 
The sponsor-investigator, or study monitor, will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 

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12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES 
 
 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The Investigator will maintain adequate case 
histories of study participants, including accurate electronic case report forms (eCRFs), and 
source documentation. 
 
 
PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited (Refer to Section 12.6). Information 
contained within this study will be maintained in accordance with applicable laws protecting 
participant privacy, including the provisions of the Health Insurance Portability and 
Accountability Act (HIPAA). 
 
Participant confidentiality is strictly held in trust by the participating Investigator(s) and study 
team. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or manufacturer supplying study product may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.  
 
Upon enrollment, participants will be assigned a code that will be used instead of their name, 
medical record number or other personally-identifying information. Electronic files for data 
analysis will contain only the participant code. Codes will not contain any part of the 18 HIPAA 
identifiers (e.g., initials, DOB, MRN). The key associating the codes and the participants’ 
personally identifying information will be restricted to the Investigator and study staff. The key 
will be kept secure on a restricted OHSU network drive in a limited access folder. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and institutional regulations. Study 
participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within the Knight Cancer Institute per OHSU’s Information 
Security Directives.  Individual participants and their research data will be identified by a unique 
study identification number.  The study data entry and study management systems used by 
clinical sites and by Knight Cancer Institute research staff will be secured and password 
protected per OHSU’s Information Security Directives.  At the end of the study, all study 
databases will be de-identified and archived within the Knight Cancer Institute. 
 

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DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. Standard institutional practices will be followed as 
described in the OHSU’s Information Security Directives to maintain the confidentiality and 
security of data collected in this study. Study staff will be trained with regard to these 
procedures. 
 
Loss of participant confidentiality is a risk of participation. Efforts will be made to keep study 
participant identities confidential except as required by law. Participants’ samples will be 
identified by code only. Specifically, each consenting participant will be assigned a unique 
coded identifier consisting of numbers. This identifier will be associated with the participant 
throughout the duration of their participation in the trial. The coded identifier will also be used to 
identify any participant-specific samples. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in 
OHSU’s electronic clinical information research system (eCRIS), hosted on OHSU secure 
servers and managed by OHSU’s information technology group at their data center in downtown 
Portland, Oregon. Any additional printed documents containing participant identifiers, such as 
those from the medical record to confirm eligibility, will be filed in binders and kept in a locked, 
secure location. 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic 
data capture (EDC) systems, that is an approved EDC system that has been reviewed by 
OHSU Security.  To further preserve confidentiality, PHI in the EDC systems will be limited to 
just birth date and visit dates.  The web-accessible EDC system is password protected and 
encrypted with role-based security, and administered by designated informatics staff within 
OHSU or Knight Cancer Institute.  All users of the databases are assigned a unique ID, 
username, and password and must complete training appropriate to their role before they are 
authorized to enter, access, and store data in the database.  Data from CLIA assays will be 
entered into the EDC by study personnel at OHSU.   
 
12.3.1 LABKEY DATA MANAGEMENT 
 
LabKey will serve as an integration point for clinical and research data in this study.  The 
LabKey platform provides solutions for study data management, biological assay data, 
biological specimen information, flexible data integration, file sharing, and data visualization in a 
secure password-protected environment.  Features of LabKey that protect participants' privacy 
and data security include: 
 
• 
Physical Security: The LabKey instance is hosted by the OHSU Information Technology Group 
(ITG) on servers housed by the Advanced Computing Center (ACC), providing locked physical 
security. 
• 
Electronic Security: The LabKey instance is housed behind both the OHSU firewall and 
a second ACC firewall. All web-based data transmissions are encrypted with industry-
standard SSL methods. 
• 
Controlled User Access: LabKey employs a group and role-based security model that 
enables researchers to implement "minimum necessary" data access for their research 
staff.  Access is integrated with OHSU's network such that users who are also OHSU 

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employees are authenticated against their OHSU network credentials. 
• 
Data Integrity: LabKey is managed in accordance with OHSU Information Security 
Directives by ACC staff, ensuring fidelity of database configuration and back-ups.  
 
Clinical data will be obtained through the Oregon Clinical and Translational Research Institute 
(OCTRI) Research Data Warehouse (RDW) (IRB #4076), a repository of clinical data and 
laboratory results for OHSU patients and research subjects to be used for clinical research.  
Information and web links to scanned biospecimen images housed in Open Microcopy 
Environment (OMERO) database and research results from individual research labs will also be 
stored in LabKey. 
 
All other electronic data extracts will be stored only on OHSU computers and restricted drives, 
limited only to study investigators and staff with authorization to access the data. Quality 
assurance will be conducted as outlined in Section 11.3, Quality Assurance & Quality Control. 
 
12.3.2 OREGON CLINICAL AND TRANSLATIONAL RESEARCH INSTITUTE (OCTRI) 
RESEARCH DATA WAREHOUSE (RDW) 
 
The OCTRI RDW is a data repository for clinical data at OHSU and is the designated repository 
Guardian responsible for ensuring that the data are received and released according to OHSU 
policy and its IRB approved repository protocol (IRB #4076).  Responsibilities include executing 
a usage agreement each time data are released for research purposes; ensuring security and 
confidentiality of stored data; securing data distribution; and tracking acquisition and release of 
data. In addition to data created for clinical care purposes, the RDW also includes OHSU 
research operations data, publicly available data and research data submitted for storage and 
future use.   
 
Features of the RDW that protect participants' privacy and data security include: 
 
• 
Physical Security: The RDW is hosted by the OHSU ITG on servers housed by the ACC 
providing locked physical security. 
• 
Electronic Security: The RDW is housed behind both the OHSU firewall and a second ACC 
firewall.  The ACC’s architecture has been reviewed by the OHSU Office of Integrity and 
undergoes periodic internal security audits. 
• 
Controlled User Access: RDW staff authentication is performed per OHSU Information 
Security Policies. Access is integrated with OHSU's network such that users who are also 
OHSU employees are authenticated against their OHSU network credentials.  Only 
authorized OHSU RDW staff are allowed direct access to individual RDW data. All RDW 
staff with direct access to individual RDW data are approved Co-investigators or Study Staff 
on the OHSU IRB protocol for the OCTRI RDW. All RDW staff have undergone training on 
pertinent OCTRI RDW policies and procedures and pertinent OHSU policies and procedures  
Additional steps are taken as appropriate with identifying data (e.g., names, addresses) to 
ensure only the “minimum necessary” identifying data are visible to RDW staff. 
• 
Data Integrity: the RDW is managed in accordance with OHSU Information Security 
Directives by ACC staff, ensuring fidelity of database configuration and back-ups.  The 
ACC's architecture has been reviewed by the OHSU Office of Integrity and undergoes 
periodic internal security audits. 
 
For this study, clinical information from OHSU’s electronic medical records system (EPIC), 

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specimen information from the Biolibrary, and results from the KDL Clinical Genomics Database 
(CGD) will be queried from OCTRI RDW.  All queried information will be deposited into the 
study-specific Data Mart, a database schema housed within OCTRI RDW.   
 
12.3.3 OPEN MICROSCOPY ENVIRONMENT (OMERO) 
 
OMERO will serve as the central repository for biospecimen images in this study.  OMERO is a 
secure password-protected platform allowing for the viewing, analyzing, and sharing of image 
files. Features of OMERO that protect participants' privacy and data security include: 
 
• 
Physical Security: The OMERO instance is hosted by the OHSU Information Technology 
Group (ITG) on servers housed by the Advanced Computing Center (ACC), providing locked 
physical security. 
• 
Electronic Security: The OMERO instance is housed behind both the OHSU firewall and a 
second ACC firewall. All web-based data transmissions are encrypted with industry-standard 
SSL methods. 
• 
Controlled User Access: OMERO employs a group and role-based security model that 
enables researchers to implement "minimum necessary" data access for their research staff.  
Access is integrated with OHSU's network such that users who are also OHSU employees 
are authenticated against their OHSU network credentials. 
• 
Data Integrity: OMERO is managed in accordance with OHSU Information Security 
Directives by ACC staff, ensuring fidelity of database configuration and back-ups.  
 
12.3.4 BIOSPECIMENS  
 
Information about specimens collected, and associated clinical data will be stored with the 
BEMS software, LABVANTAGE.  This platform is a secure, commercial off-the-shelf system that 
is hosted by OHSU’s ITG.  
 
12.3.5 FUTURE USE OF STORED BIOSPECIMENS 
 
Because we are committed to making data and/or biospecimens from this study available to the 
broader research community to address scientific questions and/or to find new ways to prevent, 
detect, or treat cancer and other diseases, participants will be asked to consent to an optional 
procedure to allow left-over biospecimens and data, including genetic data, to be stored 
indefinitely in a repository and shared for future research.  Additionally, the informed consent will 
describe to the participant that de-identified data, including genetic data and/or biospecimens 
may be deposited into publically-accessible scientific databases (also refer to section 12.6.1).    
 
The biospecimens and data collected for this protocol may be shared with the following 
repositories or databases listed below. Please note: If a participant consents to participation in 
the “Molecular mechanisms of tumor evolution and resistance to therapy (MMTERT, 
IRB#16113)” protocol any biospecimens and data may be stored and analyzed under MMTERT 
(IRB#16113) indefinitely to address the scientific questions and/or development of biological 
tests related to cancer as described in MMTERT study protocol. 
 
12.3.5.1 
The Breast Cancer Observational Study (BCOS, IRB# 22179) 
 
Biospecimens (i.e. blood and tumor) and associated data may be submitted to OHSU IRB# 
22179 BCOS for future management in accordance with relevant terms of consent and 

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authorization. Details of any transferred materials will be documented in submission 
agreement(s). Biospecimens and associated data will be stored under this study indefinitely and 
further analyzed to address scientific questions and/or development of biological tests related to 
cancer.  
 
12.3.5.2 
BioLibrary, A Tissue Repository (IRB# 4918) 
 
If the participant agrees, any remaining biospecimens (i.e., blood and tumor) and associated 
data may be may be submitted to IRB# 4918 OHSU BioLibrary for future management in 
accordance with relevant terms of consent and authorization. Details of any transferred 
materials will be documented in submission agreement(s). Samples and associated data will be 
stored in the KCI BioLibrary indefinitely and further analyzed to address scientific questions 
and/or development of biological tests related to cancer.    
 
12.3.5.3 
Oregon Clinical and Translational Research Institute (OCTRI) Research Data 
Warehouse (RDW) (IRB# 4076) 
 
All data collected originally for research purposes in this study will be accompanied by a fully 
executed submittal agreement and appropriate IRB documents prior to deposition in the OCTRI 
RDW.  This submittal agreement documents that providers of data to the OCTRI RDW agree to 
the stipulations of data submission, as specified in the RDW IRB protocol (IRB# 4076). Data 
providers remain the steward of the data. (refer to Section 12.3.2 for further description of 
OCTRI RDW) 
 
12.3.5.4 
Publically-Accessible Scientific Databases 
 
The informed consent option for storing samples for future research describes that their 
samples, data and genetic data from this study may be shared with others or placed into one or 
more publicly-accessible scientific databases, such as the NIH Database for Genotypes and 
Phenotypes (dbGaP).  Any personal information that could identify a participant will be removed 
or changed before it is shared with other researchers or results are made public.  We will seek 
to share or deposit de-identified data into publicly-accessible central repositories or databases 
that may be open or controlled access.  Study data including genomic data will be de-identified 
according to the standards set forth in the HHS Regulations for the Protection of Human 
Subjects to ensure that the identities of research subjects cannot be readily ascertained with the 
data before it is submitted. 
 
 
MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results, and medication inventory records, must be retained by the 
Investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indicate, until 2 years after the investigation is discontinued 
and FDA is notified.   
 
If the Investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed-upon designee, such as another institution or another investigator at 
OHSU. Records must be maintained according to institutional or FDA requirements.  
 

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MULTICENTER GUIDELINES  
 
Collaborating research subsites may be invited to participate in this study.  In such cases, 
OHSU will serve as the coordinating center and will manage trial data in the following ways:  
 
a. Confirm that all sites have received and are using the most recent version of the protocol. 
The protocol must not be rewritten or modified by anyone other than the OHSU Investigator. 
Documentation of the version that was sent to the site must be kept in the regulatory 
binders.  
b. Confirm that the protocol and informed consent form have local IRB approval at each site 
prior to registration of the first participant. Documentation of IRB approval from other sites 
for continuing review must be submitted and kept in the binder.  
c. Provide centralized participant registration in the clinical research management system. 
d. Ensure collection and review of applicable source documents and case reports by the 
OHSU Investigator to ensure protocol compliance. 
e. Maintain documentation for all SAE reports and submit regular summaries of all AEs, SAEs, 
and UPs from all sites to the Knight DSMC per DSMC requirements. 
f. Ensure that relevant IRB correspondence and study status changes are communicated to all 
participating sites within 5 business days. Any changes that affect participant safety of study 
enrollments will be communicated immediately. 
g. Submit documentation to the FDA such as protocol amendments, annual reports, and safety 
reports for unexpected, fatal or life-threatening events that are associated with the use of the 
investigational product. 
h. Participating sites must submit regulatory documents including, but not limited to the 
following:  
• 
Current CV (signed and dated) for each Investigator. 
• 
Current medical license number for physician investigators. 
• 
Current signed FDA Form 1572.  
• 
Certificate of completion of institution-required human participant training course, the 
NIH online training in the protection of human research participants or other appropriate 
training. 
• 
Documentation of institutional Conflict of Interest. 
i. 
IRB-approved site-specific ICF (must be reviewed and approved by OHSU Investigator and 
study team prior to submission to the local IRB. 
j. 
All IRB-approved documents and approval memos. 
k. Site delegation of authority and signature log. 
l. 
Site DSMP. 
m. Completed eCRFs (data entry) within 10 business days of study visit. 
 
 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
1. This study will comply with the NIH Public Access Policy, as applicable, to ensure that the 
public has access to the published results of NIH funded research.   
2. This study will adhere to the requirements set forth by the FDAAA that requires all clinical 
trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to participant 
enrollment. The study record in both the NCI’s Clinical Trials Reporting Program and 

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ClinicalTrials.gov should be maintained every 6 months and verified for accuracy until 
completion. In compliance with FDAAA and NIH policy, the primary outcome results of this 
trial will be reported to within 12 months of primary completion date. That is, primary 
outcomes reporting will occur 12 months after the date that the final participant was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome. For trials that have more than one primary outcome measure with different 
completion dates, this term refers to the date on which data collection is completed for all of 
the primary outcomes. 
Authors included in the publication of findings from this trial must have participated in the work 
and take public responsibility for appropriate portions of the content.   
 
12.6.1 BIOSPECIMEN AND DATA SHARING POLICY  
 
Data and/or biospecimens from this study may be made available to the broader research 
community while protecting the privacy and confidentiality of participants.  The IRB-
approved informed consent describes to the participant that their biospecimens, data and 
genetic data from this study may be shared with others or placed into one or more publicly-
accessible scientific databases, such as the NIH Database for Genotypes and Phenotypes 
(dbGaP).  Any personal information that could identify a participant will be removed or 
changed before it is shared with other researchers or results are made public.  The study 
may share or deposit de-identified data into publicly-accessible central repositories or 
databases that may be open or controlled access.  Study data including genomic data will 
be de-identified according to the standards set forth in the HHS Regulations for the 
Protection of Human Subjects to ensure that the identities of research subjects cannot be 
readily ascertained with the data before it is submitted. 
 
Refer to Section 12.3.5 for details describing potential future use of stored specimens and data.  
Additionally, biospecimens and associated clinical data will be shared with investigators of 
an on-going, OHSU, prospective observational study, MMTERT (IRB#16113)”, provided 
they are consented to IRB# 16113.   
 
Per the discretion of the Principle Investigator, study data and/or biospecimens may be released 
to co-investigators, collaborating institutions, and commercial laboratories for research that will 
help achieve the aims of this study.  Investigators outside OHSU are required to sign an 
appropriate agreement (e.g., data use agreement, material transfer agreement, research 
collaborative agreements) as determined by the Technology Transfer & Business Development 
(TTBD) office per OHSU policy and undergo review for potential commercial or intellectual 
property interests.  Identified data from this study will not be released to non-OHSU 
investigators without appropriate IRB approval and HIPAA authorization. 
 
Participants will not have access to experimental research data. Results of clinically validated 
tests may be obtained by request via the study investigator or treating physician. 
 
12.7 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed.  Furthermore, persons who have a perceived conflict of interest will be 
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design and conduct of this trial.  Conflicts of interest, for all study group members, should be 
disclosed and managed according to OHSU’s established policies and procedures. 
Refer to link: https://o2.ohsu.edu/integrity-department/conflict-of-interest/index.cfm 
 

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13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR 312 (for IND studies), ICH E6, and applicable regulatory requirements 
for protection of patient data. 
 
 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the local 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 local 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 previously consented participants need to be re-consented. 
 
 
INFORMED CONSENT 
 
Written informed consent will be obtained from all participants, or the legally authorized 
representative of the participant, participating in this trial, as stated in the Informed Consent 
section of 21 CFR Part 50. Documentation of the consent process and a copy of the signed 
consent shall be maintained in the participant’s medical record.  
 
13.3.1 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families 
as appropriate. Consent forms will be IRB-approved and the participant will be asked to read 
and review the document. The Investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks/benefits of the 
study, alternatives to participation, and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate.  It is possible that this information may be 
presented to potential participants via in-person or telephone conversations with a member of 
the study team. Potential participants will have the opportunity to review and discuss the study 
information with a member of the study team before signing the consent documents. The 
document consent form may be completed in person, through mailed correspondence, or 
electronically in which the participant can provide a scanned or photographed version of their 
signed consent form. The consent may also be signed electronically. Regardless, each new 
participant will be provided with a copy of the signed consent form and associated study 
document(s) for their own records. The copy can be provided through electronic communication 
(e.g., email address provided by the participant) or a hard copy (provided in-person or via pre-
paid mail).  The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by 

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emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute’s Clinical Research Review Committee (CRRC) and the 
appropriate IRB prior to any participant being consented on this study.   
 
 
CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and approved by the CRRC and local IRB, before the 
revision or amendment may be implemented.  The only circumstance in which the amendment 
may be initiated without regulatory approval is for a change necessary to eliminate an apparent 
and immediate hazard to the participant.  In that event, the Investigator must notify the IRB (and 
sponsor/FDA if under an IND) within 5 business days after the implementation.  
 
An Investigator who holds an IND application must also notify the FDA of changes to the 
protocol per 21 CFR 312, respectively.  

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15. APPENDICES 

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APPENDIX A: TREATMENT ARM SELECTION CRITERIA 
 
Results obtained from one or more clinically-validated assays (i.e., laboratory diagnostic test 
[LDT], or FDA-cleared or approved in vitro diagnostic [IVD] test), under the SMMART Clinical 
Analytics Platform, using either the pretreatment biopsy or on-treatment biopsy (i.e., Cycle 1, 
Day 14 ± 7 days) may be used to determine assignment to Arm 1, Arm 2, Arm 3, or Arm 4.  
Participants with or without BRCA germline mutations are eligible to be assigned to all treatment 
arms.   
 
A.1. 
Rules for treatment arm assignment  
 
Participant assignment to a treatment will follow the decision logic presented in Figure 2.  Initial 
consideration will be given to those with demonstrable immune activation as described in A.2. 
Participants whose tumor’s characteristics match these described criteria will be assigned to 
Arm 1.  Absent these criteria, consideration will next be given to those with one or more 
alterations to the RAS-MEK pathway as described in A.3.  If present, these participants will be 
assigned to Arm 2.  If the participant does not meet criteria for Arm 1 or Arm 2, their tumor 
characteristics will next be assessed for alterations in the PI3K-AKT pathway as described in 
A.4. If such PI3K-AKT alterations are present, then participants will be assigned to Arm 3. If 
none of the criteria for Arms 1, 2, or 3 are fulfilled, then participants will by default be assigned 
to Arm 4.  Allowable exception(s) to these established rules will be permitted as follows: 
 
1. Nanostring and RNAseq assay thresholds are determined from previously examined TNBC 
samples. Outliers used for treatment selection criteria in order will be based on outliers: 
a. Levels in the baseline sample 
b. Levels in the treated sample 
c. Change in levels between pre- and on-treatment samples 
 
2. Germline BRCA mutation carriers will be allowed entry to all treatment arms; however, , 
accrual of participants with a germline BRCA mutation will be capped at 4 participants per 
treatment arm, that is: 
a. A two germline BRCA participants cap in stage 1 
b. A two germline BRCA participants cap in stage 2 
As part of initial consideration for study arm assignment, if Arm 1 has accrued the maximum 
allowable number of BRCA mutants, then participants harboring a BRCA mutation may be 
considered for assignment to the next treatment arm for which they are eligible (based on 
established criteria) that has not yet reached its predefined cap. This process of treatment 
arm assignment may be systematically repeated provided that the participant is eligible for 
the next available treatment arm and the established BRCA mutant cap has not yet been 
reached. In cases where all treatment arms have reached their allowable quota of BRCA 
mutants, then study enrollment will be closed to participants harboring a BRCA mutation. 
 
3. Participant’s with tumors showing androgen receptor (AR) ≥80% by immunohistochemistry 
are excluded  
 
A.2. 
Arm 1 (olaparib + durvalumab) Selection Criteria 
 
Participants assigned to this study arm must have one or more of the following criteria: 

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• 
Evidence of immune activity based on findings from either the pre-treatment or on-treatment 
biopsy (i.e., Cycle 1, Day 14 ± 7 days) showing high tumor mutational burden, defined as 
≥10 mutations/megabase [mut/Mb], or  
• 
Presence of basal-like immune-activated (BLIA) molecular sub-type9 (i.e., RNA) observed 
on the on-treatment biopsy (i.e., Cycle 1, Day 14 ± 7 days), or 
• 
Evidence for immune activity based on findings from on-treatment biopsy (i.e., Cycle 1, Day 
14 ± 7 days), defined as: 
o PDL1 ≥ 1% [per IHC]  
 
A.3.  
Arm 2 (olaparib + selumetinib) Selection Criteria 
1. Genomic aberrations to RAS/RAF/MEK/ERK defined as: 
• 
Findings from either the pre-treatment or on-treatment biopsy (i.e., Cycle 1, Day 14 
± 7 days) showing genomic alterations in the RAS/MAPK pathway as follows: 
o Genomic alteration in RAS/MAPK pathway genes103, including: HRAS, KRAS, 
MRAS, NRAS, ARAF, BRAF, RAF1, MAP2K1, MAP2K2, MAPK1, MAPK2, MAPK3, 
ELK1, FOS, ETS1, ETS2, NF1, DUSP4, DUSP6, or   
o RTK (e.g. EGFR, MET), mutations, amplifcations, and/or fusion leading to 
RAS/MAPK pathway activation 
and/or 
2. Nanostring® GeoMx assay (LDT-CLIA): 
RAS/MAPK pathway activation in aggregate or in single pathway members on Nanostring® 
based on the pre-treatment, on-treatment biopsy (i.e., Cycle 1, Day 14 ± 7 days), or changes 
between biopsies. All values will be assessed relative to reference untreated TNBC biopsy 
cohort.  
 
A.4. 
Arm 3 (olaparib + capivasertib) Selection Criteria 
1. Genomic aberrations to PI3K/AKT defined as  
• 
PIK3CA/AKT1/PIK3R1/PTEN-altered status defined as the presence of one or 
more of the following: 
o Any Tier I or Tier II mutations in PIK3CA, PIK3R1 or AKT demonstrated to be 
activating in the literature, COSMIC, ONCOKB or FASMIC 
o PTEN loss defined by functional mutation as indicated by the literature, COSMIC, 
ONCOKB or FASMIC, homozygous deletion,  
o Loss of PTEN protein expression based on IHC or Nanostring (i.e., absence of 
PTEN in >90% of tumor cells) 
and/or 
2. Nanostring® GeoMx assay (LDT-CLIA): 
PI3K/AKT pathway activation in aggregate or in single pathway members on Nanostring® 
based on the pre-treatment, on-treatment biopsy (i.e., Cycle 1, Day 14 ± 7 days), or 
changes between biopsies.  All values will be assessed relative to reference untreated 
TNBC biopsy cohort.  
A.5. 
Arm 4 (ceralasertib monotherapy) – Default Arm 
Participants whose tumor characteristics do not fulfill the criteria for Arms 1-3 will by default be 
assigned to Arm 4.  

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APPENDIX B: SMMART EXPLORATORY RESEARCH ANALYTICS PLATFORM 
 
**Details regarding specimen collection, processing, labeling, and shipping can be found 
in the SMMART-AMTEC Laboratory Manual** 
 
Multiplex Immunohistochemistry 
Comprehensive in situ immune monitoring platform to audit immune composition and 
functionality with spatial context. Iterative cycles of immunohistochemical staining, scanning, 
and stripping will be performed on single, unstained slides from patient biospecimen at an 
OHSU laboratory. A validated antibody panel will be used to characterize tissue sample cell 
type composition, major immune group composition, as well as lymphoid and myeloid lineage 
and functional states. Additional antibody panels may be used to perform deeper profiling of 
specific aspects of the immune contexture. 
 
Cyclic Immunofluorescence 
Iterative rounds of multi-color immunofluorescent staining, imaging, and fluorophore quenching 
may be performed on single, unstained slides from patient biospecimen at an OHSU laboratory. 
Antibodies will be selected and validated to assess the cellular and extracellular composition, 
spatial organization, and molecular states (e.g. cell composition, functional protein levels, 
differentiation state, pathway activity) of tumor cells and their microenvironments. 
 
Reverse Phase Protein Arrays 
Bulk characterization of basal protein expression and modification levels for greater than 400 
independent analytes will be achieved using Reverse Phase Protein Arrays (RPPA) on patient 
biospecimen. This assay will be performed by the RPPA Core at MD Anderson. Briefly, frozen 
tissue will be lysed and protein will be extracted. Diluted lysates will be printed on nitrocellulose-
coated slides and probed with validated primary antibodies followed by detection with 
Biotinylated secondary antibodies. Signal amplification will be achieved using the Vectastain 
Elite ABC kit from Vector Lab. The slides will be scanned, analyzed, and quantified to generate 
spot intensity values and estimate relative protein levels. 
 
Electron Microscopy 
Electron microscopy (EM) may be performed on tumor tissue to provide visual evidence of 
response to therapeutic treatment at a resolution that is not obtained via other techniques. 
Tumor tissue will be fixed, processed, embedded into resin blocks, and imaged at an OHSU 
core facility. Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) and Serial Block 
Face Imaging (SBFI) may be utilized to collect high-resolution large-format images and 3D 
reconstructions of cellular ultrastructure. Correlative light and electron microscopy may be 
performed and used to provide a full understanding of protein signaling with respect to cellular 
features. 
 
Experimental Sequencing Analytics 
Additional sequencing assays may be performed on tumor tissue and blood samples at an 
OHSU laboratory or core facility in order to further characterize the genomic, transcriptomic, 
and/or epigenetic landscape or to explore intratumoral heterogeneity. These assays may 
include sequencing experiments such as single-cell DNA or RNA sequencing, whole exome 
sequencing, low-pass whole genome sequencing, and ATAC (Assay for Transposase-
Accessible Chromatin) sequencing. Methods for joint profiling may also be used, such as NMT-
seq which enables joint profiling of the DNA methylome, chromatin accessibility, and RNA. 
 

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Circulating Tumor DNA 
DNA from peripheral blood cells and circulating tumor DNA (ctDNA) from plasma may be 
isolated from patient peripheral blood samples and analyzed using next-generation sequencing 
at an OHSU laboratory or core facility. Genetic alterations identified in tumor tissue will be 
compared to those identified in ctDNA from the same time-point in order to estimate the genetic 
heterogeneity of a patient’s disease. ctDNA levels from serial blood samples will be inferred 
from sequencing results, evaluated for each participant, and correlated with clinical response to 
therapy. 
 
Circulating Cells 
Tumor tissue and circulating hybrid cells (i.e. cells that co-express components of neoplastic 
cells and immune cell lineages) may be analyzed at an OHSU laboratory or core facility to gain 
additional insight into tumor evolution. Biopsy tissue and isolated peripheral blood mononuclear 
cells will be analyzed by assays such as cyclic immunofluorescence to detect protein 
expression that align with hybrid cell phenotypes and aggressive tumor states (proliferative, 
developmental, stem cell-like). Longitudinal blood specimen will be analyzed for cell signaling 
pathway activation to identify treatment response and potential bypass pathway activation. In 
some collected specimen, hybrid cells will be queried by sequencing assays such as single cell 
RNA-seq. Resulting data may be correlated with clinical response to therapy. 
 
Experimental Blood Analytics 
 
Other Research Analytics determined to advance the Exploratory Objectives may be performed 
on peripheral blood collected from research blood draws.. This may include immunophenotyping 
by methods such as mass cytometry; characterization of cell free DNA, RNA, and proteins by 
methods such as next-generation sequencing; as well as isolation and characterization of 
extracellular vesicles by methods such as fluorescence microscopy and next-generation 
sequencing. 
 
 

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APPENDIX C: PERFORMANCE STATUS 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled. 
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 

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APPENDIX D: CONTRACEPTION 
 
Participants of childbearing potential and their partners, who are sexually active, must agree to 
the use of ONE highly effective forms of contraception and their partner must use a male 
condom [as listed below]. This should be started from the signing of the informed consent and 
continue throughout the period of taking study treatment and for at least:  
• 
1 month after last dose of olaparib,  
• 
3 month after last dose of durvalumab 
• 
1 month after last dose of capivasertib 
• 
1 month after last dose of ceralasertib 
As an alternative to contraception, the participant  must totally/truly abstain from any form of 
sexual intercourse. 
 
Male patients must use a condom during treatment and for 3 months after the last dose of 
olaparib when having sexual intercourse with an individual that is pregnant or is of childbearing 
potential for the following periods: 
• 
3 months after the last dose of olaparib 
• 
4 months after the last dose of capivasertib 
• 
6 months after the last dose of ceralasertib 
Partners of sperm-producing patients should also use a highly effective form of contraception if 
they are of childbearing potential.  Sperm-producing patients should not donate sperm 
throughout the period of taking olaparib and for 4 months following the last dose of olaparib, or 4 
months following last dose of ceralasertib. 
 
Acceptable Non-hormonal birth control methods include: 
• 
Total/True abstinence: When the patient refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; this must continue for the total 
duration of the trial and for at least 1 month (for participants of childbearing potential) after 
the last dose of study drug, or for 3 months after last dose for sperm-producing participants.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods, or 
declaration of abstinence solely for the duration of a trial) and withdrawal are not acceptable 
methods of contraception]  
• 
Vasectomised sexual partner PLUS condom.  With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom  
• 
Intrauterine device  (Provided coils are copper-banded) PLUS male condom.   
 
Acceptable hormonal methods: 
• 
Mini pill PLUS condom: Progesterone-based oral contraceptive pill using desogestrel. 
Cerazette (Merck Sharp & Dohme) is currently the only highly efficacious progesterone-
based pill available. 
• 
Combined pill PLUS condom: Normal and low-dose combined oral pills. 
• 
Injection PLUS condom: Medroxyprogesterone injection (eg, Depo-Provera [Pfizer]).  
• 
Implants PLUS condom: Etonorgestrel-releasing implants (eg, Nexplanon [Merck Sharp & 
Dohme]). 
• 
Patch PLUS male condom: Norelgestromin/ethinyl estradiol transdermal system (eg, 
Xulane). 
• 
Intravaginal device (eg, ethinyl estradiol-/etonogestrel-releasing intravaginal devices such as 
NuvaRing [Merck Sharp & Dohme]) PLUS condom. 

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• 
Levonorgestrel-releasing intrauterine system (eg, Mirena [Bayer]) PLUS condom 
 

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APPENDIX E: NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION 
 
 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or 
anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort increases. 
As published in: The Criteria Committee of the New York Heart Association. (1994).Nomenclature and Criteria for  
Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. pp. 253–256. 

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APPENDIX F: CANADIAN CARDIOVASCULAR SOCIETY GRADING OF ANGINA 
PECTORIS 
 
Grade 
Description 
I 
Ordinary physical activity does not cause angina, such as walking and climbing stairs.  Angina with st
prolonged exertion at work or recreation 
II 
Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair c
or in cold, or in wind, or under emotional stress, or only during the few hours after awakening. Walkin
blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in norma
III 
Marked limitation of ordinary physical activity. Walking one or two blocks on the level and climbing on
normal conditions and at normal pace 
IV 
Inability to carry on any physical activity without discomfort, angina syndrome may be present at rest 
Reference: L. Campeau (Circulation. 1976; 54: 522-523) 
 
 

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APPENDIX G: IDENTIFICATION ACTIONS REQUIRED IN CASES OF INCREASES 
IN LIVER BIOCHEMISTRY AND EVALUATION OF HY’S LAW CASES 
 
INTRODUCTION 
 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries.  Specific guidance on managing liver abnormalities can be found 
in Section 6.5.10 of this Clinical Study Protocol. 
 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational medicinal 
product (IP).   
 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the 
review and assessment in line with standard safety reporting processes. 
 
Definitions 
 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication  irrespective of an increase in alkaline phosphatase (ALP).   
 
Hy’s Law (HL) 
AST or ALT ≥ 3 × ULN  together with TBL ≥ 2×ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur. 
 
Identification of potential Hy’s Law cases 
 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥ 3 × ULN 
• AST ≥ 3 × ULN 
• TBL ≥ 2 × ULN 
 
 

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The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• Notify the AstraZeneca representative 
• Determine whether the patient meets PHL criteria  by reviewing laboratory reports from all 
previous visits 
• Promptly enter the laboratory data into the laboratory eCRF 
 
FOLLOW-UP 
 
Potential Hy’s Law criteria not met 
 
If the patient does not meet PHL criteria the Investigator will: 
• Inform the AstraZeneca representative that the patient has not met PHL criteria. 
• Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol. 
 
Potential Hy’s Law criteria met 
 
If the patient does meet PHL criteria the Investigator will: 
 
• 
Determine whether PHL criteria were met at any study visit prior to starting Study treatment 
(See Section 9.7 AE Reporting) 
• Notify the AstraZeneca representative  
 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 
 
• Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms and 
signs return to normal or baseline levels, or as long as medically indicated  
• Investigate the aetiology of the event and perform diagnostic investigations as discussed with 
the Study Physician 
• Complete the three Liver eCRF Modules as information becomes available  
• If at any time (in consultation with the Study Physician the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures. 
 
Review and assessment of potential Hy’s Law cases 
 
The instructions in this section should be followed for all cases where PHL criteria are met. 
 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other patient matter experts as appropriate.   
 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
 

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If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
• If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF accordingly and 
follow the AZ standard processes 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations 
other than the IMP: 
• Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes.   
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
 
• Report an SAE (report term ‘Potential Hy’s Law) applying serious criteria and causality 
assessment as per above 
• Continue follow-up and review according to agreed plan.  Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria 
are met.  Update the SAE report according to the outcome of the review amending the 
reported term if an alternative explanation for the liver biochemistry elevations is determined. 
 
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA ARE MET BEFORE AND 
AFTER STARTING STUDY TREATMENT 
 
This section is applicable to patients with liver metastases who meet PHL criteria on Study 
treatment having previously met PHL criteria at a study visit prior to starting Study treatment. 
 
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition# compared with the 
last visit where PHL criteria were met.#  
• If there is no significant change, no action is required 
• If there is a significant change, notify the AstraZeneca representative 
• A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty. 
 
Actions required for repeat episodes of potential Hy’s Law 
 
This section is applicable when a patient meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit. 

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The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.   
 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (e.g., chronic or progressing malignant disease, severe infection or liver 
disease): 
 
If No: Follow the process described in above for Hy’s Law criteria not met. 
 
If Yes: Determine if there has been a significant# change in the patient’s condition compared 
with when PHL criteria were previously met. 
 
If there is no significant change, no action is required. 
If there is a significant change, follow the process described above for “Potential Hy’s Law 
criteria met”. 
 
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the AstraZeneca Physician if there is any uncertainty. 
 

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APPENDIX H: SUMMARY LIST OF CYP1A2, CYP2C8, CYP2C19, CYP3A4, PGP, 
OATP1B1 AND BCRP SUBSTRATES, INHBITORS AND INDUCERS 
 
The medications described in this appendix are not intended to be an exhaustive list. Refer to 
FDA Drug Development and Drug Interactions for a more detailed list of inducers, inhibitors, and 
substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers). 
 
CYP SUBSTRATE(S) 
1A2 
2C19 
3A4 
Amitriptyline 
Caffeine 
Clomipramine 
Clozapine 
Cyclobenzaprine 
Duloxetine 
Estradiol 
Fluvoxamine 
Haloperidol 
Imipramine N-Deme 
Mexiletine 
Naproxen 
Olanzapine 
Ondansetron 
PhenacetinAcetaminophenNapqi 
Propranolol 
Riluzole 
Ropivacaine 
Tacrine 
Theophylline 
Tizanidine 
Triamterene 
Verapamil 
(R)Warfarin 
Zileuton 
Zolmitriptan 
 
2C8 
[Paclitaxel] 
Torsemide 
Amodiaquine 
Cerivastatin 
Repaglinide 
Sorafinib 
Proton Pump 
Inhibitors (Ppis): 
Esomeprazole 
Lansoprazole 
Omeprazole 
Pantoprazole 
Rabeprazole 
 
Anti-Epileptics: 
DiazepamNor 
Phenytoin(O) 
S-Mephenytoin 
Phenobarbitone 
 
Amitriptyline 
Carisoprodol 
Citalopram 
Chloramphenicol 
Clomipramine 
Chlopidogrel 
Cyclophosphamide 
Hexobarbital 
Imipramine N-Deme 
Indomethacin 
Labetalol 
R-Mephobarbital 
Moclobemide 
Nelfinavir 
Nilutamide 
Primidone 
Progesterone 
Proguanil 
Propranolol 
Teniposide 
R-Warfarin8-Oh 
Voriconazole 
Macrolide Antibiotics: 
Clarithromycin 
Erythromycin (Not 3a5)  
Not Azithromycin 
Telithromycin 
 
Anti-Arrhythmics: 
Quinidine3oh (Not 3a5)* 
 
Benzodiazepines: 
Alprazolam 
Diazepam3oh 
Midazolam 
Triazolam 
 
Immune Modulators: 
Cyclosporine 
Tacrolimus (Fk506)* 
 
Hiv Antivirals: 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
 
Prokinetic: 
Cisapride 
 
Antihistamines: 
Astemizole* 
Chlorpheniramine 
Terfenadine* 
 
Calcium Channel 
Blockers: 
Amlodipine 
Diltiazem 
Felodipine 
Lercanidipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Verapamil 
 
Steroid 6beta-Oh: 
Estradiol 
Hydrocortisone 
Progesterone 
Testosterone 
 
Miscellaneous: 
Alfentanyl* 
Aprepitant 
Aripiprazole 
Boceprevir 
Buspirone 
Carbamazepine 
Cafergot 
CaffeineTmu 
Cilostazol 
Cocaine 
Codeine-N-Demethylation 
Dapsone 
Dexamethasone 
Dextromethorphan 
Docetaxel 
Domperidone 
Eplerenone 
Fentanyl* 
Finasteride 
Gleevec 
Haloperidol 
Irinotecan 
Laam 
Lidocaine 
Methadone 
Nateglinide 
Nevirapine 
Ondansetron 
Pimozide* 
Propranolol 
Quetiapine 
Quinine 
Risperidone 
Romidepsin 
Not Rosuvastatin 
Salmeterol 
Sildenafil 

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CYP SUBSTRATE(S) 
1A2 
2C19 
3A4 
Hmg Coa Reductase 
Inhibitors: 
Atorvastatin 
Cerivastatin 
Lovastatin 
Not Pravastatin 
Not Rosuvastatin 
Simvastatin 
Sirolimus 
Sorafenib 
Tamoxifen 
Taxol 
Telaprevir 
Terfenadine 
Torisel 
Trazodone 
Vemurafenib 
Vincristine 
Zaleplon 
Ziprasidone 
Zolpidem 
* Drugs known to be metabolized by CYP3A4 and have a narrow therapeutic index 
 
CYP2B6 substrates known to have a narrow therapeutic index 
Cyclophosphoamide 
Ifosfamide 
Efavirenz 
Bupropion 
Propofol 
Thiotepa 
Sorafenib 
Alfentanil 
Ketamine 
Methadone 
Methoxetamine 
Nevirapine 
Propofol 
Selegiline 
Sertraline 
Sorafenib 
Tamoxifen 
Valproic Acid 
 
CYP INHIBITORS 
1A2 
2C8 
2C19 
3A4 
Fluvoxamine 
Ciprofloxacin 
Cimetidine 
Amiodarone 
Efavirenz 
Fluoroquinolones 
Fluvoxamine 
Furafylline 
Interferon 
Methoxsalen 
Mibefradil 
Ticlopidine 
Gemfibrozil 
Trimethopri
m 
Glitazones 
Montelukast 
Quercetin 
Ppis: 
Esomeprazole 
Lansoprazole 
Omeprazole 
Pantoprazole 
 
Other: 
Rabeprazole 
Chloramphenico
l 
Cimetidine 
Felbamate 
Fluoxetine 
Fluvoxamine 
Indomethacin 
Ketoconazole 
Modafinil 
Oral 
Contraceptives 
Oxcarbazepine 
Probenicid 
Ticlopidine 
Topiramate 
Voriconazole 
Hiv Antivirals: 
Indinavir 
Nelfinavir 
Ritonavir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Saquinavir 
Telithromycin 
Aprepitant 
Erythromycin 
Fluconazole 
Grapefruit Juice 
Verapamil 
Diltiazem 
Cimetidine 
Amiodarone 
Not Azithromycin 
Chloramphenicol 
Boceprevir 
Ciprofloxacin 
Delaviridine 
Diethyldithiocarbamate 

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Fluvoxamine 
Gestodene 
Imatinib 
Mibefradil 
Mifepristone 
Norfloxacin 
Norfluoxetine 
Star Fruit 
Telaprevir 
Voriconazole 
 
INDUCERS 
1A2 
2C8 
2C19 
3A4 
Broccoli 
Brussel Sprouts 
Carbanazepine 
Char-Grilled Meat 
Insulin 
Methylcholanthrene 
Modafinil 
Nafcillin 
Beta-Naphthoflavone 
Omeprazole 
Rifampin 
Tobacco 
Rifampin 
Carbamazepine 
Nevirapine 
Phenobarbital 
Rifampin 
Secobarbital 
St. John’s Wort 
Hiv Antivirals: 
Efavirenz 
Nevirapine 
Barbiturates 
Carbamazepine 
Glucocorticoids 
Modafinil 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John's Wort 
Troglitazone 
 
Drugs Known to be Inhibitors of Pgpa 
Drugs Known to be Inducers of Pgpb 
Amiodarone 
Azithromycin  
Captopril  
Carvedilol  
Clarithromycin  
Conivaptan  
Cremophor  
Curcumin  
Diltiazem  
Dronedarone  
Elacridar  
Erythromycin  
Felodipine  
Fluvoxamine  
Ginkgo  
Indinavir  
Itraconazole  
Ketoconazole  
Lapatinib 
Lopinavir And Ritonivir  
Mibefradil 
Milk Thistle  
Mirabegron  
Nelfinavir 
Nifedipine  
Nitrendipine 
Paroxetine  
Quercetin 
Quinidine  
Ranolazine 
Rifampin  
Ritonavir  
Saquinavir/Ritonavir  
Schisandra Chinensis Extract  
St Johns Wort 
Talinolol  
Telaprevir 
Telmisartan  
Ticagrelor 
Tipranavir/Ritonavir  
Tolvaptan 
Valspodar (PSC 833) 
Verapamil 
Avasimibe 
Carbamazepine  
Efavirenz  
Genistein  
Phenytoin  
Rifampin 
St Johns Wort 
a. Inhibitors listed for P-gp are those that showed >25% increase in exposure to a P-gp substrate  

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Drugs Known to be Inhibitors of Pgpa 
Drugs Known to be Inducers of Pgpb 
(e.g. digoxin). 
b. Inducers listed for Pgp are those that showed >20 % decrease in exposure to a P-gp substrate 
(e.g. digoxin) 
 
Drugs Known to be Inhibitors of BCRP 
Drugs Known to be inducers of 
BCRP 
Afatinib  
Aripiprazole  
Curcumin  
Cyclosporine  
Elacridar  
Erlotinib  
Fluvastatin  
Fumitremorgin  
Gefitinib  
Ivermectin  
Lapatinib  
Nilotinib  
Novobiocin  
Pantoprazole  
Pitavastatin  
Ponatinib  
Quercetin  
Quizartinib  
Rabeprazole  
Regorafenib  
Rilpivirine  
Sulfasalazine  
Sunitinib  
Tacrolimus  
Teriflunomide  
Trametinib  
Trifluoperazine  
Vismodegib 
eltrombopag 
Atazanavir 
Lopinavir 
Ritonavir 
Tipranavir 
Omeprazole 
Estrone 
17b-estradiol 
Imatinib mesylate 
Please check individual drugs on a 
case by case basis  
List created using http://dmd.aspetjournals.org/content/dmd/43/4/490.full.pdf 
Note: Although BCRP is involved in a number of clinically relevant DDIs, none of the cited inhibitors 
above is truly specific for this transporter 
 
OATP1B1 substrates 
BCRP substrates 
Atorvastatin  
Fluvastatin  
Lovastatin  
Pitavastatin  
Pravastatin  
Rosuvastatin  
Simvastatin  
Ezemibe  
Simvastatin  
Methotrexate  
Rifampin  
Bosentan  
Glyburide  
Repaglinide  
Valsartan  
Olmesartan  
Atrasentan 
Anthracyclines 
Daunorubicin 
Doxorubicin 
Topotecan 
SN-38 
Irinotecan 
Methotrexate 
Imatinib 
Irinotecan 
Mitoxantrone 
nucleoside analogs 
prazosin 
pantoprazole 
topotecan 
rosuvastatin and other 
statins 
teriflunomide 
chlorothiazide 

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APPENDIX I: QT PROLONGING MEDICATIONS 
 
The following table describes common medications associated with QT prolongation, but is not 
intended to be an exhaustive list. Investigators are recommended to consult with pharmacist 
regarding other medications with QT-prolonging effects.  
 
QT Prolonging Medications 
Antimicrobials 
Atazanavir 
Azithromycin 
Bactrim 
Ciprofloxacin 
Chloroquine 
Clarithromycin 
Erythromycin 
Fluconazole 
Fosarnet 
Gatifloxacin 
Gemifloxacin 
Halofantrine  
Imipramine 
ltraconarole 
Ketoconazole 
Levofloxacin 
Moxifloxacin 
Ofloxacin 
Pentamidine 
Ritonavir  
Sparfloxacin 
Telithromycin 
Voriconazole 
Antidepressants 
Amitriptyline  
Citalopram 
Clomipramine 
Desipramine 
Doxepin 
Escitalopram 
Fluoxetine 
Nortriptyline 
Paroxetine 
Protriptyline 
Sertraline 
Trazodone 
Trimipramine 
Venlafaxine 
 
Antiemetics 
Antiemetics  
Dolasetron  
Domperidone  
Droperidol  
Granisetron  
Odansetron 
 
Anticonvulsants 
Felbamate  
Fosphenytoin 
Phenytoin 
Antipsychotics 
Chlorpromazine 
Clozapine  
Haldol 
Mesoridazine  
Paliperidone  
Pimozide 
Quetiapine 
Risperidone  
Sertindole 
Thioridazine 
Ziprasidone 
 
Antiarrhythmics 
Amiodarone 
Disopyramide 
Dofetilide 
Dronedarne 
Flecainide 
lbutilide 
Nicardipine 
Procainanicle 
Quinidine 
Sotalol 
Other Drugs 
Alfuzosin 
Astemizole 
Amantadine 
Bepridil 
Cisapride 
Oiphenhydramine 
Eribulin 
Famotidine 
Fingolimod 
Galantamine 
lndapamide 
Lapatinib 
Lithium 
Methadone 
Moexipril 
Nilotinib 
Octreotide 
Oxytocin 
Probucol 
Ranolazine 
Sunitinib 
Tacrolimus 
Tamoxifen 
Terfenadine 
Tizanidine 
Vandetanib 
Vardenafil