Clinical trial NCT03205761
Conditions: Advanced Breast Cancer
Keywords: Advanced Breast Cancer Triple Negative olaparib lynparza BRCA Methylation
Sponsor: Spanish Breast Cancer Research Group
Start date: 2017-10-23; Completion date: 2022-12-15
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter single-arm phase II clinical trial to evaluate the efficacy and safety of olaparib in patients diagnosed of advanced triple negative breast cancer (TNBC) with methylation of BRCA1 and/or BRCA2 promoters assessed in DNA from metastatic lesions and absence of BRCA1 and 2 germline mutations.

Detailed description:
Patients must have received at least one previous regimen in the advance disease setting and must have at least one measurable lesion that can be accurately assessed according to RECIST v.1.1. Potential eligible patients will be screened to assess somatic (s) BRCA promoter methylation at an reference central laboratory. Germinal (g) BRCA mutational status will be analyzed also centrally at 'Myriad Genetics GmBh' laboratory unless the BRCA mutational status is already known based on a Myriad previous report. Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be enrolled in the study and receive olaparib.

Blood and tumor samples collected from all screened patients could be used for the biomarker analysis, including the assessment of germline methylation status and gene expression levels of BRCA1/2. An early efficacy review will be performed after 12 evaluable patients are enrolled; if at least 4 of them show tumour response, additional patients will be included to complete a total of 34 patients.

Arms: arm 1: Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be included in the study to receive olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: Olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first.

Protocol documents:
Prot_000.pdf: 
GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 1 of 128 
 
 
Protocol GEICAM/2015-06 
 “A Phase II Clinical Trial to analyse Olaparib Response in patients with 
BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast 
Cancer” 
“COMETA-Breast study” 
SPONSOR:  
GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama) 
Avenida de los Pirineos 7, planta 1ª, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid), Spain 
Phone: 0034 916 592 870; Fax: 0034 916 510 406 
Email: geicam@geicam.org 
CHIEF INVESTIGATOR: 
Dr. Juan R. de la Haba-Rodríguez 
Instituto Maimónides de Investigación Biomédica (IMIBIC) 
Hospital Universitario Reina Sofía; Córdoba, Spain 
Sponsor Study Code: GEICAM/2015-06 
EudraCT Number: 2016-001407-23 
AstraZeneca Code: ESR-15-11274 
Protocol reviewed by FECMA (Spanish Federation of Breast Cancer Patients)  
 
 
CONFIDENTIAL 
The information and data included in this protocol contain secrets and privileged or confidential information which is the property of 
GEICAM. No one is authorized to make this information public without the written permission of GEICAM. These limitations shall 
also be applied to all the information considered to be privileged or confidential and provided in the future. This material can be 
disclosed and used by its equipment and collaborators as necessary for conducting the clinical trial. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 2 of 128 
 
 
Protocol Number: GEICAM/2015-06 
Protocol Tittle: “A Phase II Clinical Trial to analyse Olaparib Response in patients with BRCA1 
and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer (COMETA-Breast 
study)”. 
EudraCT Number: 2016-001407-23 
Version: 3.0 
Version Date:  10 June 2019 
 
 
 
__________________________________________                              _____________________ 
Chief Investigator: Dr. Juan R. de la Haba-Rodríguez                          Date (dd/mmm/yyyy) 
H. U. Reina Sofía / IMIBIC 
 
 
__________________________________________                              _____________________ 
Scientific Department: Dr. Susana Bezares                                           Date (dd/mmm/yyyy) 
(Associate Medical Director)                    
GEICAM  
 
 
__________________________________________                              _____________________ 
Statistician: María José Escudero                                                            Date (dd/mmm/yyyy) 
GEICAM 
 
 
__________________________________________                             _____________________ 
Protocol/Project Manager: Nuria Martín                                                 Date (dd/mmm/yyyy) 
GEICAM 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 3 of 128 
 
SUMMARY OF THE STUDY PROTOCOL 
Study Title: “A Phase II Clinical Trial to analyse Olaparib Response in patients with BRCA1 
and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer (COMETA-Breast 
Study)” 
Sponsor Study Code: GEICAM/2015-06 
Sponsor: GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)   
Indication: Triple negative (TN) Advanced Breast Cancer (ABC)  
Countries and approximate number of sites:  Spain /16 sites approximately  
Number of patients: Approximately 34 patients will be included in the study. 
Study Rationale: 
Triple negative Breast Cancer (TNBC) represents approximately 12-17% of BC overall. This 
tumour subtype is characterized by the presence of stem cell precursors, a high proliferation rate 
and metastatic capacity and a worse prognosis than other BC subtypes.  Median survival of 
advanced TNBC is at best 12 months, much shorter than the survival seen in other subtypes of 
advanced BC. Chemotherapy is the current mainstay of therapy for TNBC with varied impact on 
long-term prognosis. No targeted treatment has been developed for TNBC. Therefore, 
identification of specific targeted and more active therapies for TNBC patients remains an 
important clinical challenge. 
One of the most frequent molecular events in TN breast tumours is the presence of BRCA protein 
dysfunction. Among BC patients with a hereditary BRCA1 mutation, over 80% is a TNBC. 
Sporadic TN tumours often show the same histological characteristics and clinical outcome as 
BRCA1 mutation carriers so several studies have postulated that BRCA1 inactivation might also 
have a role in sporadic TNBCs. The phenotype that some sporadic tumours share traits with 
familial BRCA cancer is called “BRCAness”.  
Approximately 15% of ovarian cancer patients and 5% of breast, pancreatic and prostate cancer 
patients have inherited mutations of BRCA1 or BRCA2, and it has been suggested that a further 
~20% of tumours display so-called “BRCAness” phenotype. The importance of defining such a 
group of tumours lies within the clinical management of these tumours. 
Inhibition of Polyadenosine 5’diphosphoribose [poly (ADP ribose] polymerisation (PARP) is a 
promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 
and BRCA2 mutation-associated breast and ovarian cancers.  
After preliminary data showing minimal efficacy of PARP inhibitors (PARPi) in sporadic BC, 
some of the trials were amended to enrich the study cohorts for BRCA-associated tumours. Initial 
phase I testing olaparib as monotherapy in BRCA-associated breast, prostate and ovarian cancers 
showed that 47% of patients with BRCA-associated breast, ovarian, or prostate cancers treated 
with olaparib achieved a partial response, and 63% of them derived clinical benefit.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 4 of 128 
 
On December 2014, Marketing Authorisation Applications were approved in EU/EEA and US for 
the capsule formulation of LYNPARZA® (olaparib) monotherapy for the treatment of BRCA-
mutated advanced ovarian cancer patients. Phase II clinical studies have investigated the effect of 
olaparib either as monotherapy or in combination with other chemotherapy agents in other cancer 
types. Tutt et al. reported efficacy of olaparib as monotherapy in 54 patients with advanced BC 
heavily pre-treated and germline BRCA1/2 mutations. At the maximum tolerated olaparib dose 
(400 mg b.i.d., capsule formulation) it was observed a 41% ORR, with a 54% ORR observed in 
the TNBC subgroup (7 out of 13 patients). The majority of completed studies have been 
performed with the capsule formulation of olaparib but most new studies, including the Phase III 
registration studies, are being performed with the tablet formulation which delivers the 
therapeutic dose of olaparib in fewer dose units than the capsule. Based on the totality of the 
efficacy, safety/tolerability profile and the patient convenience of a b.i.d. dosing schedule, the 300 
mg b.i.d. tablet dose was chosen as the recommended Phase III monotherapy dose. Recently, 
OlympiAD (NCT02000622) trial comparing treatment with olaparib tablets versus a standard of 
care chemotherapy in  patients with HER2-negative MBC harbouring germline BRCA1 or BRCA2 
mutations showed that patients treated with olaparib have a statistically-significant and clinically-
meaningful improvement in PFS compared with those who received chemotherapy63.  
Since August 2017, the tablet formulation has subsequently been approved in the US, EU and 
Japan for different types of ovarian cancer and in January 2018 has been approved by US for 
patients with deleterious or suspected deleterious gBRCAm, HER2-negative MBC who have 
previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. 
In addition to BRCA mutations, other alterations can be responsible for a dysfunctional BRCA 
protein. One of them is the epigenetic silencing by aberrant methylation of BRCA1/2 promoter, 
more frequently described in medullary and metaplastic tumours. In most cases, the methylation 
status leads to gene silencing. The methylation of BRCA1/2 promoter has been explored in 
multiple neoplasms, finding variable frequencies: ovarian 5-20%, gastric 50% and breast 29-59%. 
BRCA1-methylated sporadic breast tumours have been described in young women and display 
pathologic features similar to those of BRCA1-mutated BC. Interestingly, sporadic tumours with 
aberrant BRCA1 promoter methylation can be clustered with tumours derived from women with 
inherited BRCA1 germline mutations because of similarities in their global gene expression 
profiles.  
Similarly to BRCA germline mutations, reduced function of other key proteins in the homologous 
recombination pathway results in increased sensitivity to PARPi and enhancement of 
chemotherapy and radiotherapy treatments. For these reasons, PARP inhibition represents a novel 
approach as an anti-tumour therapy and may address an unmet need in patients with BRCA-
associated cancer. 
Based on these results and data from the full clinical program to date, it is anticipated that orally 
active PARP inhibitor, olaparib, will have a positive benefit risk profile for the treatment of the 
small well-defined population of advanced TNBC patients with promoter methylation of BRCA. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 5 of 128 
 
Study Drug(s)/medications: 
Dose/Route/Regimen 
Eligible patients will be enrolled and treated with: 
✓ Olaparib as single agent at 600 mg continuous daily dose (tablet formulation); given in 
two oral administrations (300 mg every 12 hours).  
 
All patients included will receive study therapy until radiographic or symptomatic progression, 
unacceptable toxicity or withdraw of the informed consent, whatever occurs first.  
Study Design and Treatment: 
This is a multicenter single-arm phase II clinical trial to assess the efficacy and safety of 
olaparib in patients diagnosed of advanced TNBC with methylation of BRCA1 and/or 2 
promoters assessed in DNA from metastatic lesions and absence of BRCA1 and 2 germline 
mutations. Patients must have received at least one previous regimen in the advance disease 
setting.  
 
 
 
Potential eligible patients will be screened to assess germinal (g) BRCA mutational status at 
Myriad laboratory (unless the BRCA mutational status is already known based on a Myriad 
previous report).  
Blood samples for mutational BRCA screening could be sent either 1) during the previous line of 
treatment prior to study enrolment, once the eligibility criteria have been reviewed and the patient 
is considered a potential candidate for the study (at least the patient must have measurable and 
biopsiable disease) or 2) after ending the line of treatment prior to study enrolment 
(simultaneously to the shipment of the tumour samples for methylation analysis). A specific ICF 
must be signed for this screening assessment. 
Somatic (s) BRCA promoter methylation will be assessed also centrally at an external reference 
central laboratory selected by GEICAM. Tumour samples must be obtained from a metastatic 
lesion, it is strongly recommended to obtain the tumour sample after the treatment line 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 6 of 128 
 
immediately previous to the study entry. 
Patients with a positive methylation status on BRCA1 and/or BRCA2 and lacking of known 
deleterious or suspected deleterious mutations in both genes could be included in the study to 
receive olaparib tablet formulation at 600 mg daily dose (given in two oral administrations of 300 
mg every 12 hours approximately).  
 
Blood and tumour samples collected from all registered patients could be used for biomarker 
analysis planned in the study, including but not limited to the assessment of germline 
methylation status and gene expression levels of BRCA1/2. 
 An optimal two-stage Simon design will be used to analyse olaparib efficacy in the study 
population, the analysis of the stage 1 will be performed after 12 evaluable patients are 
enrolled; if at least 4 of them show tumour response, additional patients will be included to 
complete a total of 31 evaluable patients. Assuming a 10% dropout rate, the total number of 
patients to be enrolled is 34. 
It is planned the participation of 16 Spanish sites, recruitment will be competitive 
approximately 2 or 3 patients should be enrolled per site; to achieve that is estimated that 7 or 8 
patients approximately should be screened per site. 
Primary Objective: 
• 
To analyse the olaparib efficacy in the treatment of patients diagnosed of advanced triple 
negative breast cancer (TNBC) with BRCA1 and/or BRCA2 promoter methylation 
assessed in somatic DNA.  
Primary End-point: 
• 
Objective Response Rate (ORR) defined as Complete Response (CR) plus Partial 
Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) 
version 1.1. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 7 of 128 
 
Secondary Objectives: 
• 
To analyse other efficacy measures. 
• 
To analyse olaparib safety. 
• 
To explore changes in the methylation status of BRCA1/2 promoter in germline DNA 
prior and after treatment discontinuation for any reason and correlate germline BRCA1/2 
methylation data with efficacy parameters. 
• 
To correlate BRCA1/2 methylation between germline and somatic DNA and between 
primary tumour and metastatic lesions.  
• 
To correlate BRCA1/2 expression with methylation status of BRCA1/2 promoter and 
efficacy parameters.  
Secondary End-points: 
• 
Clinical Benefit Rate (CBR), Response Duration (RD), Progression Free Survival (PFS) 
and Overall Survival (OS). 
• 
Adverse events defined by the NCI-CTCAE (National Cancer Institute Common 
Terminology Criteria for Adverse Events) version 4.0. 
• 
The methylation status of BRCA 1 and 2 promoters will be measured in germline DNA 
from blood cells at the beginning of the study and after disease progression, or at the end 
of study treatment by other reason, and in paired primary and metastatic lesions. It will 
be analysed: 1) changes of germline methylation pre and post-treatment; 2) correlation 
between germline methylation status and efficacy outcome data; 3) correlation between 
germline and somatic methylation status and 4) correlation between primary and 
metastatic lesions.  
• 
mRNA levels of BRCA1 and 2 will be assessed in blood and available tumour samples. 
Expression data will be correlated with promoter methylation status of BRCA and 
outcome data.   
Exploratory Objectives: 
• 
To explore biomarkers of clinical activity in tumour and blood samples.  
Exploratory End-points: 
• 
Biomarker values from the primary or metastatic tumour tissue could be used for 
assessment of biomarkers related to breast tumour sensitivity and/or resistance to 
olaparib (e.g. may include but not limited to somatic BRCA1/2 mutational status or other 
genes related to cancer susceptibility or thought to be related to the drug mechanism of 
action). These samples will be instrumental to explore biomarkers of response or 
resistance to olaparib.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 8 of 128 
 
• 
DNA and RNA obtained from the blood samples collected during the study may be used 
for potential pharmacogenomics analyses related to drug response or adverse drug 
reactions (including but not limited to comparison of germline DNA or RNA patterns of 
patients who respond well and those who respond poorly to treatment). For example, 
genes coding drug metabolizing enzymes, drug transport proteins or genes involved in 
DNA repair pathways, cancer susceptibility or thought to be related to the drug 
mechanisms of action may be analysed.  
• 
Specific mutations or epigenetic biomarkers identified in pre-therapy tumour specimens 
as potentially linked to treatment response could be tested in plasma DNA. A targeted 
NGS panel may be designed to study all the candidate mutations. Plasma DNA has also 
the potential to be a surrogate of tumour load and may also be instrumental to monitor 
disease. 
Study population and main inclusion and exclusion criteria: 
Inclusion Criteria:  
Patients are eligible to be included in the study only if they meet all of the following criteria. 
Any asterisked* are also applicable as an inclusion criteria prior to perform the BRCA 
methylation testing via central testing; to perform the BRCA methylation test, investigator 
judgement of patient’s potential eligibility to the study should be assessed as per Protocol  
Attachment 1. Study Schedule and by reviewing the below inclusion criteria: 
1. *The patient has signed and dated the informed consent document and it has been obtained 
before conducting any procedure specifically for the study. 
2. Female ≥ 18 years of age on day of signing informed consent. 
3. Patient with histological confirmation of breast cancer with evidence of advanced disease 
not amenable to resection or radiation therapy with curative intent.  
4. Documented triple negative disease by immunohistochemistry (IHC) and/or in situ 
hybridization based on local testing (preferably assessed on the most recent tumour biopsy 
available). TN is defined as negative hormone receptor status (< 1% of tumour cells with 
ER and PgR expression) and HER2-negative status (defined as IHC score 0/1+ or 
negative by in situ hybridization defined according to local criteria).  
5. Patient must have received at least one previous regimen in the advance disease setting. 
6. Absence of deleterious or suspected deleterious germline mutations in BRCA1 and BRCA2. 
Germinal BRCA mutational status will be centrally assessed in Myriad laboratories to 
check eligibility unless the test has been previously performed at Myriad and absence of 
mutations has been determined. 
7. Availability of a tumour tissue sample from the metastatic lesions (every effort should be 
done to obtain the sample after the previous therapeutic regimen for advanced disease) for 
central testing. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 9 of 128 
 
8. Documented methylation of BRCA1 and/or 2 promoters based on central testing by 
analysis on the most recent tumour from metastatic lesions available. 
9. At least one lesion measurable not previously irradiated, that can be accurately measured at 
baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis 
≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) or clinical 
examination and which is suitable for accurate repeated measurements according to RECIST 
v.1.1.  
10. Patient must have normal organ and bone marrow function measured within 28 days prior 
to administration of study treatment as defined below: 
- Haemoglobin ≥ 10.0 g/dL with no blood transfusions in the past 28 days 
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
- Platelet count ≥ 100 x 109/L 
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
- 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 ≤ 5 x ULN 
- Patients must have creatinine clearance estimated using the Cockcroft-Gault equation 
of ≥51 mL/min: 
               Estimated creatinine clearance =  (140-age [years]) x weight (kg) (x F)a 
                                     serum creatinine (mg/dL) x 72 
a where F=0.85 for females. 
11. *Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (see protocol 
attachment 2)  
12. *Patient must have a life expectancy ≥ 16 weeks 
13. *Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential: negative urine or serum pregnancy test within 28 days of study treatment and 
confirmed prior to treatment on day 1. 
Postmenopausal patient is defined as a woman fulfilling any one of the following criteria 
(based on the NCCN definition of menopause [National Comprehensive Cancer Network 
2008]): 
- Prior bilateral oophorectomy. 
- Age > 60 years. 
- Age ≤ 60 years and with amenorrhea for 12 or more months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle stimulating 
hormone and estradiol in the postmenopausal range.  
14. Olaparib is regarded as a compound with medium/high foetal risk, patients of childbearing 
potential and their partners, who are sexually active, must agree to the use of TWO highly 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 10 of 128 
 
effective 
forms 
of 
contraception 
in 
combination 
as 
listed 
below. 
This 
should be started from the signing of the informed consent for study entry and continue 
throughout period of taking study treatment and for at least 1 month after last dose of study 
drug or they must totally/truly abstain from any form of sexual intercourse (see below).  
Acceptable non-hormonal birth control methods include:  
- Total sexual abstinence. Abstinence must continue for the total duration of the study 
treatment and for at least 1 month after one dose. Periodic abstinence (e.g., calendar 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
- Vasectomised sexual partner PLUS male condom. With participant assurance that 
partner received post-vasectomy confirmation of azoospermia. 
- Tubal occlusion PLUS male condom. 
- Intrauterine Device (IUD) PLUS male condom. Provided coils are copper-banded. 
Acceptable hormonal methods: 
- Normal and low dose combined oral pills PLUS male condom. 
- Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly 
efficacious progesterone based pill. 
- Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom. 
- Etonogestrel implants (e.g. Implanon or Norplan) PLUS male condom. 
- Norelgestromin/ethinyl estradiol (EE) transdermal system PLUS male condom. 
- Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS -Mirena®) PLUS 
male condom. 
- Intravaginal device PLUS male condom (e.g. EE and etonogestrel).  
15. *Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits, laboratory tests and examinations and 
other study procedures including follow up. 
Exclusion Criteria:   
Patients will be excluded from the study if they meet any of the following criteria. Any 
asterisked* are also applicable as an exclusion criteria prior to perform the BRCA methylation 
testing via central testing; to perform the BRCA methylation testing, investigator judgement of 
patient’s potential eligibility to the study should be assessed as per Protocol  Attachment 1. 
Study Schedule and by reviewing the below exclusion criteria): 
 
1. 
Involvement in the planning and/or conduct of the study (applies to the sponsor and/or 
study site staff). 
2. 
Previous enrolment in the present study.  
3. 
Participation in another clinical study with an investigational product during the last 4 
weeks. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 11 of 128 
 
4. 
*Any previous treatment with a PARP inhibitor, including olaparib.  
5. 
*Patients with other malignancy within the last 5 years, except: adequately treated non-
melanoma skin cancer (basal cell or squamous cell carcinoma), curatively treated in-situ 
cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial 
carcinoma, or other solid tumours including lymphomas (without bone marrow 
involvement) curatively treated with no evidence of disease for ≥ 5 years prior to study 
inclusion. Patients with a history of localised breast cancer with tumour histology different 
to TN, with no evidence of disease for ≥ 5 years since they completed their adjuvant 
treatment. 
6. 
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons), within 3 weeks prior to study treatment (or a longer period depending on the 
defined characteristics of the agents used). 
7. 
Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or 
family history of long QT syndrome. 
8. 
*Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting olaparib is 2 weeks. Please refer to section 5.5.2.1 about strong and 
moderate CYP3A inhibitors.   
9. 
*Concomitant use of known 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 
3 weeks for other agents. Please refer to section 5.5.2.2 about strong and moderate CYP3A 
inducers.   
10. *Persistent toxicities (> NCI-CTCAE grade 2) caused by previous cancer therapy (except 
alopecia or other toxicities not considered a safety risk for the patient at investigator´s 
discretion). 
11.  *Patients with myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) or with 
features suggestive of MDS/AML.  
12. *Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence 
of brain metastases is not required. Patients with brain metastases may be eligible for the 
study only if more than 4 weeks from treatment completion for these metastases (including 
radiation and/or surgery), are clinically stable at the time of study entry. 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.  Patients with spinal cord compression unless 
considered to have received definitive treatment for this and evidence of clinically stable 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 12 of 128 
 
disease for 28 days.    
13. Major surgery within 2 weeks of starting study treatment and patients must have recovered 
from any effects of any major surgery. 
14. *Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
15. *Breast feeding women.  
16. *Immunocompromised patients, e.g. patients who are known to be serologically positive 
for human immunodeficiency virus (HIV). 
17. *Patients with known active hepatitis (i.e., Hepatitis B or C) due to risk of transmitting the 
infection through blood or other body fluids. 
18. *Patients with a known hypersensitivity to olaparib or any of the excipients of the product.  
19. *Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection or laboratory 
abnormality that may increase the risk associated with study participation or may 
interfere with the interpretation of study results and, in the judgment of the investigator, 
would make the patient inappropriate for entry into this study. 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, severe hepatic impairment (according to Child-Pugh 
classification), an extensive interstitial bilateral lung disease on High Resolution 
Computed Tomography (HRCT) or any psychiatric disorder that prohibits obtaining 
informed consent.  
20. *Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT). 
21. *Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no 
10).  
Justification of Sample size determination: 
We have set the null hypothesis (H0) that ORR will be 30% (ORR achieved by TN patients 
treated with gemcitabine plus carboplatin1) versus the alternative hypothesis (H1) that ORR will 
be 54% (ORR showed by TN BRCA mutated patients treated with olaparib2). Using an optimal 
two-stage Simon model and considering an alpha error of 0.05 and a statistical power of 80%, it 
will be required to include 31 evaluable patients. Twelve evaluable patients will be analysed in 
the first stage, and if at least 4 patients of them have tumour response, additional patients will 
be recruited to get a total of 31 evaluable patients. Assuming a 10% dropout rate, the total 
number of patients to be enrolled is 34. Considering, these data the number of responders 
needed at the end of stage 2 to reject the null hypothesis is at least 14 responders. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 13 of 128 
 
Statistical Analyses: 
➢ Demographics and Baseline Characteristics 
Standard descriptive statistics, such as the mean, median, range and proportion, will be 
used to summarize the patient sample and to estimate parameters of interest. 
➢ Safety Analyses 
Adverse events data and serious adverse events will be reported in frequency tables 
(overall and by intensity). The safety analysis will be performed in the population that 
has received at least one dose of the study drug.  
➢ Efficacy Analyses 
ORR will be calculated in the efficacy population and in the ITT population. 
Study Duration: 
The start date of study is the date of the first site initiation visit. This study will be considered 
complete following the data cut-off date and data-lock for the final analysis; the data cut-off date 
will be the date of last patient´s death or the date when there is sufficient data to achieve the 
final analysis, whichever comes first. It is estimated that the final analysis could be performed 
approximately 30 months after the enrolment of the first patient because, considering a median 
OS of 12 months, it is estimated that more than 50% of death events will have occurred at that 
time and OS analysis could be performed. The study is expected to start in Quarter 3 2017 and to 
end by Quarter 1 2020. 
Performing exploratory objectives will be independent of the date of the end of the study. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 14 of 128 
 
INDEX 
 
SUMMARY OF THE STUDY PROTOCOL ................................................................................. 3 
INDEX .............................................................................................................................................. 14 
Abbreviations and Definitions........................................................................................................ 18 
1. Introduction ................................................................................................................................. 22 
1.1. Overview of Breast Cancer .................................................................................................... 22 
1.2. Triple Negative Breast Cancer (TNBC) ................................................................................. 22 
1.2.1. Treatment Options for Triple Negative Advanced Breast Cancer .................................. 22 
1.2.2. Methylation of BRCA Promoter and Breast Cancer Risk .............................................. 23 
1.3. PARP Inhibitors in Breast Cancer ......................................................................................... 24 
1.4. Overview of Olaparib ............................................................................................................ 26 
1.4.1. Preclinical Data .............................................................................................................. 27 
1.4.2. Toxicology and safety pharmacology summary ............................................................. 27 
1.4.3. Pharmacokinetics and Drug Metabolism in Humans ..................................................... 28 
1.4.3.1. Pharmacokinetics following single and multiple dosing of the tablet formulation
 ........................................................................................................................................... 29 
1.4.3.2. Metabolism and Excretion of Olaparib ................................................................. 30 
1.4.3.3. Effect of Intrinsic Factors on the PK of Olaparib ................................................. 31 
1.4.3.4. Effect of Extrinsic Factors on the PK of Olaparib ................................................ 32 
1.4.4. Effect of Olaparib on Cardiac Repolarisation ................................................................ 35 
1.4.5. Clinical Experience ........................................................................................................ 36 
1.4.5.1. Olaparib Monotherapy Efficacy Data ................................................................... 37 
1.4.5.2. Olaparib 400 mg b.i.d. Monotherapy (capsule formulation) Pooled Safety Data . 39 
1.4.5.2. Olaparib 300 mg b.i.d. monotherapy (tablet formulation) pooled dataset ........ 40 
1.4.5.3. Emerging Safety Profile ........................................................................................ 41 
1.5. Study Rationale ...................................................................................................................... 44 
1.6. Benefit/risk and ethical assessment........................................................................................ 44 
1.6.1. Important Potential Risks ............................................................................................... 45 
1.6.2. Potential Benefit ............................................................................................................. 46 
2. Objectives ..................................................................................................................................... 48 
2.1. Primary Objective .................................................................................................................. 48 
2.2. Primary End-point .................................................................................................................. 48 
2.3. Secondary Objectives ............................................................................................................. 48 
2.4. Secondary End-points ............................................................................................................ 48 
2.5. Exploratory Objectives .......................................................................................................... 49 
2.6. Exploratory End-points .......................................................................................................... 49 
3. Investigational Plan ..................................................................................................................... 50 
3.1. Study Design .......................................................................................................................... 50 
3.1.1. Early Efficacy Review .................................................................................................... 51 
3.2. Duration of the Study ............................................................................................................. 51 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 15 of 128 
 
4. Study Population ......................................................................................................................... 53 
4.1. Inclusion Criteria ................................................................................................................... 53 
4.2. Exclusion Criteria .................................................................................................................. 55 
4.3. Restrictions during the Study ................................................................................................. 57 
4.4. Discontinuations .................................................................................................................... 58 
4.4.1. Discontinuation of Study Drugs/Medications ................................................................ 58 
4.4.2. Discontinuation of Study Sites ....................................................................................... 59 
4.4.3. Discontinuation of Study ................................................................................................ 59 
5. Treatment ..................................................................................................................................... 60 
5.1. Treatments Administered ....................................................................................................... 60 
5.2. Materials and Supplies ........................................................................................................... 60 
5.2.1. Doses and treatment regimens ........................................................................................ 60 
5.2.2. Labelling ......................................................................................................................... 61 
5.2.3. Storage ............................................................................................................................ 61 
5.2.4. Accountability ................................................................................................................ 62 
5.3. Method of Assigning a Patient to a Treatment ...................................................................... 62 
5.4. Special Treatment Considerations. Dose Adjustments of Olaparib ....................................... 63 
5.4.1. Management of haematological toxicity ........................................................................ 64 
5.4.1.1. Management of Anaemia ...................................................................................... 64 
5.4.1.2. Management of Neutropenia, Leukopenia and Thrombocytopenia ...................... 64 
5.4.1.3. Management of Prolonged Haematological Toxicities while on Study Treatment
 ........................................................................................................................................... 65 
5.4.2. Management of Non-Haematological Toxicity .............................................................. 65 
5.4.2.1. Management of New or Worsening Pulmonary Symptoms ................................. 66 
5.4.2.2. Management of Nausea and Vomiting ................................................................. 66 
5.4.2.3. Management of Renal Impairment ....................................................................... 66 
5.4.3. Interruptions for Intercurrent Non-toxicity Related Events ............................................ 67 
5.4.4. Medication Errors and Overdose .................................................................................... 67 
5.5. General Concomitant Medication and Supportive Care Guidelines ...................................... 68 
5.5.1. Medications that may NOT be administered .................................................................. 68 
5.5.2. Restricted concomitant medications ............................................................................... 69 
5.5.2.1. Strong or Moderate CYP3A inhibitors ................................................................. 69 
5.5.2.2. Strong or Moderate CYP3A inducers ................................................................... 70 
5.5.3. P-gp inhibitors ................................................................................................................ 70 
5.5.4. Other Concomitant Medications ..................................................................................... 70 
5.6. Treatment Compliance ........................................................................................................... 72 
6. Efficacy and Safety Evaluations, Sample Collection and Testing (Standard Laboratory 
Testing) and Appropriateness of Assessments .............................................................................. 73 
6.1. Efficacy Assessments ............................................................................................................. 73 
6.1.1. Primary Efficacy Assessments ....................................................................................... 73 
6.1.2. Secondary Efficacy Assessments ................................................................................... 73 
6.2. Safety Assessments ................................................................................................................ 74 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 16 of 128 
 
6.2.1. Timing of Assessments ................................................................................................... 74 
6.2.2. Definitions ...................................................................................................................... 76 
6.2.3. Management, Timing and Assessment of Adverse Events............................................. 79 
6.2.4. Management, Timing and Assessment of SAEs ............................................................. 84 
6.2.5. Management, Timing and Assessment of SUSARs ....................................................... 88 
6.3. Biological sampling procedures ............................................................................................. 89 
6.3.1. Biological Samples ......................................................................................................... 89 
6.3.2. BRCA1 and BRCA2 Promoter Methylation Testing in Somatic DNA .......................... 91 
6.3.3. Germline BRCA1 and BRCA2 Mutational Testing ....................................................... 92 
6.3.4. Other Biomarker Assessments ........................................................................................ 92 
7. Data Quality Assurance .............................................................................................................. 94 
7.1. Data Management and Registries File ................................................................................... 94 
8. Sample Size and Statistical Methods ......................................................................................... 95 
8.1. Determination of Sample Size ............................................................................................... 95 
8.1.1. Sample Size Determination ............................................................................................ 95 
8.2. Statistical and Analytical Plans .............................................................................................. 95 
8.2.1. General Considerations .................................................................................................. 95 
8.2.1. Patient Populations ......................................................................................................... 95 
8.2.2. Patient Disposition .......................................................................................................... 96 
8.2.3. Patient Characteristics .................................................................................................... 96 
8.2.4. Concomitant Therapy ..................................................................................................... 96 
8.2.5. Treatment Compliance ................................................................................................... 96 
8.2.6. Efficacy Analyses ........................................................................................................... 97 
8.2.6.1. Analyses of Primary Endpoint .............................................................................. 97 
8.2.6.2. Analysis of Secondary Endpoints ......................................................................... 97 
8.2.7. Safety Analyses .............................................................................................................. 99 
8.2.7.1. Other significant adverse events (OAE) ............................................................... 99 
8.2.8. BRCA1/2 Methylation and expression analysis ............................................................. 99 
8.2.9. Other Analysis .............................................................................................................. 101 
8.2.9.1. Other Biomarker Analysis .................................................................................. 101 
8.2.9.2. Subgroup Analyses ............................................................................................. 101 
8.2.10. Interim Analysis ......................................................................................................... 101 
8.2.11. Criteria for End of Study ............................................................................................ 101 
9. Informed Consent, Confidentiality, Responsibility Insurance and Regulatory 
Considerations ............................................................................................................................... 103 
9.1. Informed Consent................................................................................................................. 103 
9.2. Respect of Confidentiality ................................................................................................... 103 
9.3. Responsibility Insurance ...................................................................................................... 104 
9.4. Regulatory Considerations ................................................................................................... 104 
9.4.1. Investigator Information ............................................................................................... 104 
9.4.2. Protocol Signatures ....................................................................................................... 104 
10. Practical Considerations ......................................................................................................... 105 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 17 of 128 
 
10.1. Monitoring, Audit and Inspections .................................................................................... 105 
10.2. Preservation of Study Documentation ............................................................................... 105 
10.3. Protocol Modification ........................................................................................................ 105 
10.4. Study Resources, Use of the Information and Publication ................................................ 105 
10.5. Ethics Committee ............................................................................................................... 106 
11. Important medical procedures to be followed by the investigator ..................................... 107 
11.1. Overdose ............................................................................................................................ 107 
11.2. Pregnancy ........................................................................................................................... 107 
11.3. Maternal exposure .............................................................................................................. 107 
12. References ................................................................................................................................ 109 
Protocol Attachment 1. Study Schedule ...................................................................................... 116 
Protocol Attachment 2. Eastern Cooperative Oncology Group Performance Status ............. 121 
Protocol Attachment 3. Adverse event (AE) non defined in NCI-CTCAE .............................. 122 
Protocol Attachment 4. Adverse Events / Serious Adverse Events Assessment Guide ........... 123 
Protocol Attachment 5. Actions required in cases of combined increase of Aminotransferase 
and Total Bilirubin – Hy’s Law ................................................................................................... 124 
Protocol Attachment 6. Patient Diary ......................................................................................... 128 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 18 of 128 
 
Abbreviations and Definitions  
ABC 
Advanced Breast Cancer 
AE 
Adverse Event 
AEMPS 
Spanish Agency for Medicines and Health Products 
AESI 
Adverse Event of Special Interest 
ALT/ALAT (SGPT) 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
APTT 
Activated Partial Thromboplastin Time  
AR 
Adverse Reaction 
AST/ASAT (SGOT) 
Aspartate Aminotransferase 
BC 
Breast Cancer 
b.i.d. 
Twice daily (from Latin Bis In Die) 
BUN 
Blood Urea Nitrogen 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
Compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Scan 
Computed Tomography Scan 
DLT 
Dose-Limiting Toxicity  
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
DSB 
Double Strand Break 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form (sometimes referred to as Clinical Report Form). An 
electronic form for recording study participants’ data during a clinical study, as 
required by the protocol. 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EE 
Ethinyl Estradiol 
End of Study (Trial) 
This study will be considered complete following the data cut-off date and datalock 
for the final analysis, the data cut-off date will be the date of last patient´s death or the 
date when there is sufficient data to achieve the final analysis for primary and 
secondary objectives, whichever comes first 
Enroll 
The act of including a patient in the study. Patients who are enrolled in the trial are 
those who have been assigned a registration (or screening) numberand it will be 
confirmed that the patient will receive the study treatment. 
Screen 
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial. Patients 
entered into a trial are those who sign the informed consent document directly or 
through their legally acceptable representatives. Patients who are entered in the trial 
will be assigned a registration (or screening) number. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 19 of 128 
 
EOT 
End of Treatment 
ER 
Oestrogen Receptor 
ERB/IRB/IEC 
Ethical review board/Institutional review board/Independent Ethics Committee:  A 
board or committee (institutional, regional, or national) composed of medical 
professional and nonmedical members whose responsibility is to verify that the safety, 
welfare, and human rights of the patients participating in a clinical trial are protected. 
ESR 
et al 
Expedited Safety Report 
And collaborators 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
gBRCA 
BRCA1 and 2  in germinal line 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyltransferase  
GMP 
GLS 
Good Manufacturing Practice  
Geometric least squares  
GEICAM 
Fundación Grupo Español de Investigación en Cáncer de Mama 
G-CSF 
Granulocyte Colony-Stimulating Factor 
HER2 
Human Epidermal Growth Factor Receptor 2 
Hgb 
Haemoglobin 
HL 
Hy’s Law 
HR 
Homologous Recombination or Hazard Ratio depending on the context 
HRD 
Homologous Recombination DNA pathway Deficiency 
HRR 
Homologous Recombination DNA Repair 
IC50 
Concentration for 50% inhibition 
ICD 
Informed Consent Document  
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the Investigator is the responsible 
leader of the team and may be called the Principal Investigator. 
INR 
International Normalised Ratio  
ISH 
In Situ Hybridization 
ITT 
Intent To Treat 
LDH 
Lactic dehydrogenase 
Legal Representative 
An individual, judicial, or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical trial. 
LLN 
Lower Limit of Normal 
MDS/AML 
Myelodysplastic Syndrome/ Acute Myeloid Leukemia 
MBC 
Metastatic Breast Cancer 
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 
MCV 
Mean Cell Volume 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mRNA 
Messenger Ribonucleic Acid 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 20 of 128 
 
N.B. 
Please note from Latin “Nota bene”. 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute  Common Terminology Criteria for Adverse Events 
OAE 
Other Significant Adverse Event 
o.d. 
Once a day 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PARP 
Polyadenosine 5’diphosphoribose [poly (ADP ribose] polymerisation (PARP)  
Patient 
A subject with a defined disease. 
PD 
Progressive Disease or Pharmacodynamic depending on the context 
PFS 
Progression-Free Survival 
P-gp 
P-glycoprotein 
PgR 
Progesterone Receptor 
PK 
Pharmacokinetic 
PR 
Partial Response 
PS 
Performance Status 
RBC 
Red Blood Cells  
RD 
Response Duration 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RP2D 
Recommended Phase II Dose 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SSB 
Single Strand Break 
SD 
Stable Disease or Standard deviation depending on the context 
sBRCA 
BRCA1 and 2  in somatic line (tumour) 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TN 
Triple Negative 
TTP 
Time To Progression 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells  
WNL 
Within Normal Limits 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 21 of 128 
 
 
 
 
 
Study Title: Protocol GEICAM/2015-06 
 
“A Phase II Clinical Trial to analyse Olaparib Response in patients with 
BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast 
Cancer” 
 
“COMETA-Breast Study” 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 22 of 128 
 
1. Introduction 
1.1. Overview of Breast Cancer 
Breast cancer (BC) represents one of the most frequent cancers in general population and 
the first malignant tumour in women worldwide. In Europe, there were an estimated of 
464,000 new cases of breast cancer in 2012, with a mortality of 131,000 cases3. Specifically 
in Spain, incidence is around 26,000 new cases per year and although a steady decrease in 
mortality has been demonstrated in the last decades, nearly 20% of the patients relapse and 
ultimately die of breast cancer, which represent a mortality of approximately 6,000 women 
per year in Spain4. 
1.2. Triple Negative Breast Cancer (TNBC) 
Breast cancer has been classified in several subtypes by gene expression analyses including 
luminal, basal-like, HER2-enriched and claudin-low5,6. Each one represents an independent 
entity with different prognosis and potential response to specific therapeutic strategies7. 
Using immunostaining in tumour samples, it has been observed, that most of basal-like 
tumours are those that match with cancers that are defined by lack or low 
immunohistochemical (IHC) expression of oestrogen (ER), progesterone (PgR) and HER2 
(IHC 0, 1+ or 2+/ISH not amplified); therefore, this particular subset of breast cancer has 
been termed triple negative breast cancer (TNBC)8, which represents approximately 12-
17% of breast cancer overall9. This tumour subtype is characterized by the presence of stem 
cell precursors, a high proliferation rate and metastatic capacity10,11 and a worse prognosis 
than other breast cancer subtypes. These factors may be a major reason for the high-risk of 
relapse, and the shorter progression-free survival (PFS) and overall survival (OS) reported 
for this disease12,13. 
It is known that within this group there is differential expression of several genes that could 
have clinical relevance14. One of those differences with potential therapeutic implications is 
BRCA1 expression. Turner et al reported low expression of BRCA1/2 in approximately 70% 
of basal-like tumours15. Consistent with this, one of the most frequent molecular events in 
TN breast tumours is the presence of BRCA protein dysfunction16. Among breast cancer 
patients with a hereditary BRCA1 mutation, over 80% is a TNBC17. As sporadic triple-
negative tumours often show the same histological characteristics and clinical outcome as 
BRCA1 mutation carriers, several studies postulated that BRCA1 inactivation might also 
have a role in sporadic TNBCs18,19. The phenotype that some sporadic tumours share traits 
with familial BRCA cancer is called “BRCAness”20. The importance of defining such a 
group of tumours lies within the clinical management of these tumours21. 
1.2.1. Treatment Options for Triple Negative Advanced Breast Cancer 
Treatment options for advanced breast cancer (ABC) are numerous and varied, however the 
median survival for patients with metastatic disease is still only approximately 18 to 24 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 23 of 128 
 
months22 and the medical need for more active agents in this clinical setting remains very 
high, especially in triple negative tumours, a challenging situation where impact of the 
current treatments in overall survival is relatively low23. Median survival of advanced 
TNBC is at best 12 months, much shorter than the duration of survival seen in other 
subtypes of ABC. Chemotherapy is the current mainstay of therapy for TNBC patients with 
varied impact on long-term prognosis and no optimal cytotoxic regimen has been 
identified. Chemotherapeutic agents with proven activity in TNBC include anthracyclines, 
taxanes, platinum derivatives, capecitabine, gemcitabine, vinorelbine, eribulin, and 
ixabepilone24,25. 
At present, multiply efforts are being performed to improve the prognosis for these patients. 
It implies both optimization in selection and scheduling of cytotoxic agents or dose 
intensification strategies and introduction of new targeted agents. No targeted treatment has 
been developed for TNBC, in contrast to endocrine treatment and anti-HER2 treatments, 
which have significantly improved the clinical outcomes in ER/PgR positive and HER2 
positive breast cancer patients, respectively. Therefore, identification of specific targeted 
and more active therapies for TNBC patients remains an important clinical challenge. 
1.2.2. Methylation of BRCA Promoter and Breast Cancer Risk 
It is known that germline mutations in one of the genes encoding BRCA proteins (BRCA1 
and BRCA2) increase the susceptibility to breast and ovarian cancer, in fact, these 
mutations are observed in 5-10% of breast tumours26 and up to 20% of high grade serous 
ovarian tumours27. Both proteins have a key role in cellular homeostasis, making a 
fundamental contribution in the regulation of the ER expression and repair of double-
stranded DNA breaks, mainly by the homologous recombination (HR) pathway28. DNA 
breaks can be leaded by multiple chemotherapeutic agents. 
The association between BRCA1 mutations and a common expression phenotype (CK 5/6+, 
ER- and mutated p53) could reflect a common aetiology for breast and ovarian tumours. 
However, the frequency of BRCA1 mutations is much lower than the breast cancer basal 
subtype or the high grade serous ovarian cancer. 
In addition to the mutational analysis of BRCA, other alterations can be responsible for a 
dysfunctional BCRA protein. One of them is the epigenetic silencing by aberrant 
methylation of BRCA1/2 promoter, more frequently described in medullary and metaplastic 
tumours. It is known that, in most cases, the methylation status leads to gene silencing. The 
methylation of BRCA1/2 promoter has been explored in multiple neoplasms, finding highly 
variable frequencies: ovarian 5-20%29,30, gastric 50%31 and breast 29-59%32,33,34. BRCA1-
methylated sporadic breast tumours have been described in young women and display 
pathologic features similar to those of BRCA1-mutated hereditary breast cancers35,36,37.  
Among different breast cancer types, the level of tumour DNA methylation seems to be 
higher in TNBC cases and in tumours with high BRCA-like histopahological scores38. 
According to Tutt et al. up to 40% of TNBCs harbor methylated BRCA1 genes; they 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 24 of 128 
 
recently showed that CpG methylation was associated with transcriptional silencing of 
BRCA1 mRNA. They were able to analyze primary tumors for 191 patients, of which 
mRNA and methylation status data were available for 184 and observed that Sixty-six 
percent of methylated tumor samples were gene-silenced39. Interestingly, sporadic tumours 
with aberrant methylation of the BRCA1 promoter can be clustered with tumours derived 
from women with inherited BRCA1 germline mutations because of similarities in their 
global gene expression profiles18,40.  
There are other causes leading deficiencies in the repair process of double-stranded DNA 
breaks by the homologous recombination mechanism, such as the loss of heterozygosity or 
the expression of negative regulators of BRCA, as ID4, or loss of function of proteins as 
RAD51, CHECK2 or ATM41.  
The methylation assessment can be performed both at tumour tissue and at germline level 
(DNA from nucleated peripheral blood cells), without necessarily existing a correlation 
between both measurements. Furthermore, methylation status is a changing and dynamic 
process, determined at tumour level by the own carcinogenic process and at germline level 
by multiple processes, including the different anti-tumour treatments.  
The methylation status of BRCA1 promoter assessed in germline DNA, isolated from 
peripheral blood cells, has been associated with breast cancer risk42,43,44. In the Bosviel 
dataset the methylation rate of BRCA1 at the germline level in breast cancer patients 
(n=902) was 47.1%45. These results are consistent with other datasets such as those studied 
by Snell46 or Iwamoto who detected methylation of BRCA1 promoter in 43 out of 200 
breast cancer patients (21.5%), a higher frequency than the rate observed in controls 
(27/200, 13.5%)47. These findings suggest that BRCA1 promoter methylation is an event 
that occurs in normal tissues and can be associated with the development of breast cancers 
BRCA1-like48.  
Although there is limited information, the relationship between the methylation status in 
BRCA1 promoter in germline and tumour DNA has been reported in several datasets38,49. 
According to Wong et al49, this association suggest that the methylation at this level and in 
a constitutive manner could be the first event in the carcinogenesis process of a group of 
non-inherited breast cancers. Other authors have reported this correlation between germline 
and tumour methylation status, as Al-Moghrabi et al. who found correlation in 10 out of 15 
analysed cases (66.7%)50. Sarah et al. showed that blood DNA methylation levels  
correlated with tumour methylation at most of the BRCA1 CpG sites examined although 
those levels were higher in tumour DNA compared to matched blood DNA samples38. 
1.3. PARP Inhibitors in Breast Cancer 
Inhibition of  Polyadenosine 5’diphosphoribose [poly (ADP ribose] polymerisation (PARP) 
is a promising strategy for targeting cancers with defective DNA-damage repair, including 
BRCA1 and BRCA2 mutation-associated breast and ovarian cancers51. Several PARP 
inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the 
treatment of ovarian, BRCA-mutated breast, and other cancers. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 25 of 128 
 
The observation that BRCA-mutated breast cancers show impairment in HR pathways52, 
and that some sporadic TNBC are phenocopies of BRCA1-mutated cancers (i.e. they 
display a phenotype resembling BRCA1-mutated cancers without harbouring a BRCA1 
mutation, a feature also defined as “BRCAness”), led to exploration of the application of 
PARP inhibition to the treatment of breast cancer (BRCA-associated and TNBC). 
Following the demonstration by Bryant and Farmer53,54 of the cytotoxic effect of PARP 
inhibition in HR-deficient cells, there was interest in studying the activity of PARP 
inhibitors as monotherapy in solid tumours. In earlier studies, the population enrolled in 
these trials was not restricted to patients with known BRCA mutations, but encompassed 
also those whose cancer displayed a phenotype similar to BRCA-mutated cancers. 
Clinically, this group included triple-negative breast cancers and high grade serous or 
poorly differentiated ovarian cancer. 
However, after preliminary data showing minimal efficacy of PARP inhibitors in sporadic 
breast cancers, some of the trials were amended to enrich the study cohorts for BRCA-
associated tumours55,56. Initial phase 1 testing of olaparib as monotherapy in BRCA-
associated breast, prostate and ovarian cancers showed encouraging results: 47% of patients 
with BRCA-associated breast, ovarian, or prostate cancers treated with olaparib achieved a 
partial response, and 63% of them derived clinical benefit (tumour marker decrease or 
radiologic response or stable disease for 4 or more months). A phase 1 study of niraparib in 
patients with advanced solid tumours enriched for BRCA-associated cancers reported an 
overall response rate of 40% (8 of 20) in patients with BRCA-associated ovarian cancer and 
50% (2 of 4) in patients with BRCA-associated breast cancer57. Talazoparib monotherapy 
has shown antitumour activity in patients with BRCA mutations, with an objective response 
rate of 65% in ovarian and peritoneal tumours and 33% (2 of 6 patients) in breast cancers58. 
Data presented at ASCO 2014 on single agent rucaparib showed efficacy in BRCA-
associated ovarian, breast, and pancreatic cancers59. 
Tutt et al.2 reported efficacy of olaparib as monotherapy in 54 patients with advanced breast 
cancer and germline BRCA1/2 mutations. At the maximum tolerated olaparib dose of 400 
mg b.i.d. (capsule formulation), a 41% ORR was observed, with responses in both TNBC 
and hormone receptor-positive HER2-negative patients. It is noteworthy that the ORR 
achieved by TN patients was 54%. 
Kaufman et al60 reported data of a phase 2 study of olaparib monotherapy in 298 patients 
with diverse recurrent cancers (mostly ovarian, breast, pancreatic, and prostate) and 
confirmed BRCA1/2 mutations (a study design called “basket trial”). Breast cancer tumour 
response rate was 12.9% in 62 patients, and 47% of patients had disease stabilization for ≥ 
8 weeks. The lower objective response rate in this study compared with previous studies 
could be due to the fact that the study population was more heavily pre-treated than in other 
trials (mean of 4.6 prior chemotherapy regimens in the metastatic setting vs. 3 in Tutt et 
al2). 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 26 of 128 
 
Randomized phase 3 studies of PARPi in MBC have been limited to patients with 
documented BRCA1/2 mutations. Three parallel study designs have already tested 
(EMBRACA and OlympiAD) or are currently testing (BRAVO NCT01905592)61 oral 
PARPi monotherapy vs. physician’s choice single agent chemotherapy in breast cancer 
patients with PARPi-naive metastatic disease with germline BRCA1/2 mutations. Study 
results from EMBRACA (talazoparib, NCT01945775) trial showed that among patients 
with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib 
provided a significant benefit over standard chemotherapy with respect to progression-free 
survival62. OlympiAD (olaparib, NCT02000622) trial compared treatment with olaparib 
tablets to physician’s choice of a standard of care chemotherapy in the treatment of patients 
with HER2-negative metastatic breast cancer harboring germline BRCA1 or BRCA2 
mutations and have shown that patients treated with olaparib showed a statistically-
significant and clinically-meaningful improvement in PFS compared with those who 
received chemotherapy (capecitabine, vinorelbine or eribulin)63.  
Finally, BROCADE3 study (NCT02163694)64 will test the efficacy of veliparib versus 
placebo in combination with carboplatin and paclitaxel in HER2-negative metastatic or 
locally advanced, unresectable, BRCA-associated breast cancer. 
1.4. Overview of Olaparib 
Investigators should be familiar with the current olaparib (AZD2281, KU-0059436) 
Investigator Brochure (IB). The approved tradename for olaparib is LYNPARZA™. 
Olaparib is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose] polymerisation 
(PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a 
monotherapy (including maintenance) and for combination with chemotherapy and other 
anti-cancer agents. 
PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). 
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 (HRR). Tumours with HR deficiencies (HRD), such as 
ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA 
damage, which may become lethal to cells as it accumulates. In such tumour types, olaparib 
may offer a potentially efficacious and less toxic cancer treatment compared with currently 
available chemotherapy regimens.  
BRCA1 and BRCA2 defective tumours are intrinsically sensitive to PARP inhibitors, both 
in tumour models in vivo65,66 and in the clinic55. The mechanism of action for olaparib 
results from the trapping of inactive PARP onto the single-strand breaks preventing their 
repair67,68. Persistence of SSBs during DNA replication results in their conversion into the 
more serious DNA DSBs that would normally be repaired by HR repair. Olaparib has been 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 27 of 128 
 
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.  
1.4.1. Preclinical Data 
The preclinical experience is fully described in the current version of the olaparib 
Investigator’s Brochure (IB). 
Olaparib was developed as a PARP inhibitor from a targeted screening programme of 
pharmacophores, with the aim of enhancing the killing actions of certain existing cancer 
chemotherapies such as the topoisomerase I inhibitors and alkylating agents. Development 
has yielded a compound that has the potential for stand-alone cancer therapy as well as use 
in combination cancer treatments69. 
Olaparib activity against PARP-1, PARP-2, PARP-3 and another PARP family member, 
Tankyrase-1 is shown in Table 1. 
Table 1. Activity of olaparib against purified PARP enzyme 
Enzyme 
IC50 (nM) 
PARP-1 
5 
PARP-2 
1 
PARP-3 
4 
Tankyrase-1 
1500 
IC50 Concentration for 50% inhibition; PARP Polyadenosine 5’diphosphoribose polymerase; PARP-1 
Polyadenosine 5’diphosphoribose polymerase-1; PARP-2 Polyadenosine 5’diphosphoribose polymerase-2; 
PARP-3 Polyadenosine 5’diphosphoribose polymerase-3. 
1.4.2. Toxicology and safety pharmacology summary 
Olaparib has been tested in a standard range of safety pharmacology studies e.g. dog 
cardiovascular and respiratory function tests, and the rat Irwin test.  
Secondary pharmacodynamics and safety pharmacology studies were conducted with 
olaparib to assess for potential off-target activity and effects on the cardiovascular, 
respiratory as well as central nervous systems, respectively. 
• Olaparib showed no significant off-target activity at concentrations 6-fold the human 
mean free Cmax at the clinical dose of 300 mg bd (3.65 μM) when screened in vitro 
against a diverse panel of molecular targets including enzymes, receptors, transporters 
and ion channels. 
• Olaparib inhibited the hERG encoded potassium channel expressed in vitro, with an IC50 
of 226 μM, which was 60-fold greater than the human mean free Cmax (3.65 μM) at the 
clinical dose of 300 mg bd. 
• Olaparib showed no significant effects in vivo in dog cardiovascular/respiratory and rat 
Irwin (behavioural) tests. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 28 of 128 
 
The nonclinical safety evaluation of olaparib is based on data from a variety of single and 
repeat dose toxicology studies in rats and dogs, reproductive toxicology studies in rats and 
an in vitro and in vivo assessment of genotoxic potential. In addition, studies investigating 
single and repeat dose combinations of olaparib with topotecan or temozolomide (TMZ) 
were conducted in rats. Key findings are summarised below:  
• The principal target organ for toxicity was the bone marrow in repeat dose toxicity and 
tolerability studies in rats and dogs, all changes showed full or partial recovery 
following withdrawal of treatment or a 28 day recovery period. 
•  Olaparib was not mutagenic in an Ames bacterial mutation test, but was clastogenic in a 
Chinese Hamster Ovary (CHO) chromosome aberration test in vitro. These findings are 
consistent with genomic instability resulting from the primary pharmacology of olaparib. 
• In reproductive toxicology studies in rats, olaparib produced no adverse effects on male 
fertility, while on female rats, although conception rates were unaffected, embryofoetal 
survival was decreased. Administration of olaparib during organogenesis caused 
reductions in early embryofoetal survival and foetal weights as well as increases in the 
incidence of abnormalities at dose levels that were not maternally toxic. 
• Combination studies in rats suggested potential for olaparib to exacerbate the effects of 
TMZ or topotecan, although combination of olaparib with these anti-cancer agents did 
not induce any additional target organ toxicities to those seen with single agent 
administration. 
There were relatively few findings of concern in the non-clinical toxicology studies, 
although exposures in these studies were generally below those achieved at the clinical 
dose of olaparib (300 mg b.i.d. tablet). In conclusion, the non-clinical safety evaluation 
studies conducted with olaparib support the use of olaparib for the treatment of cancer 
patients. 
Further information can be found in the current version of the olaparib Investigator’s 
Brochure. 
1.4.3. Pharmacokinetics and Drug Metabolism in Humans 
The initially developed capsule formulation of olaparib consists of 50 mg dosing units with 
a monotherapy dosing schedule of 400 mg b.i.d. The tablet formulation consists of dosing 
units up to 150 mg olaparib with a monotherapy dosing schedule of 300 mg b.i.d. Given the 
different drug delivery technologies in the capsule and tablet, the formulations cannot be 
considered bioequivalent. 
As of 15 December 2017, pharmacokinetics (PK) data are available from 11 clinical 
studies: Studies D081BC000001 (Japanese Phase I monotherapy), D081BC00002 (Chinese 
Phase I monotherapy and interaction with paclitaxel), D0816C00004 (food interaction and 
QT), D0816C00007 (CYP3A4 inhibition and QT), D0816C00008 (CYP3A4 induction) and 
D0810C00024 (relative bioavailability for the capsule and tablet formulations) 
D0816C00005 (hepatic impairment), D0816C00006 (renal impairment) and D081CC00001 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 29 of 128 
 
(interaction with anti-hormonal agents), D0816C00002 (SOLO2) and D0819C00003 
(OlympiAD) The tablet formulation is under study in the majority of the on-going and 
future olaparib studies. Based on the totality of the efficacy, safety/tolerability profile and 
the patient convenience of a b.i.d. dosing schedule, the 300 mg b.i.d. tablet dose was chosen 
as the recommended Phase III monotherapy dose (Study D0810C00024).  
1.4.3.1. Pharmacokinetics following single and multiple dosing of the olaparib 
monotherapy tablet formulation 
Single dose final PK data (using intensive PK sampling and non-compartmental analysis) 
are available following oral dosing of olaparib at dose levels ranging from 25 mg to 450 mg 
in Western patients with normal renal and hepatic function. Single dose PK data for 56, 56, 
22, 13 and 12 patients are available from Studies D0816C00004 (300 mg), D0816C00007 
(100 mg) and D0816C00008 (300 mg), D0816C00005 (300 mg) and D0816C00006 (300 
mg), respectively. Multiple dose final data (using intensive PK sampling) following oral 
dosing of olaparib to Western patients are available from Studies D0816C00004 (300 mg 
b.i.d.), D0816C00007 (300 mg b.i.d.), D0810C00024 (Group 8, 400 mg o.d.) and 
D081CC00001 (300 mg b.i.d) for 49, 45, 12 and 27 patients, respectively. Additional 
multiple dose data are available based on sparse PK sampling in Study D0810C00024 and 
Study D0816C00002 (SOLO2), and PK parameters were derived using nonlinear mixed 
effects PK modeling. 
Following single oral dosing to cancer patients using the tablet formulation, olaparib was 
rapidly absorbed with peak plasma concentrations typically observed at 1.5 hours. 
Following time to maximum plasma concentration (tmax), plasma concentrations of 
olaparib declined in a biphasic manner with an average terminal elimination t1/2 of 14.9 
hours (SD 8.2 hours). The mean apparent oral plasma clearance was approximately 7.4 L/h 
(SD 3.9 L/h). The mean volume of distribution was greater than total body water indicating 
that olaparib was distributed into the tissues; 158 L (SD 136 L). The observed 
interindividual variability in exposure was moderate to high, the Gmean %CV for AUC and 
Cmax following 300 mg single dose olaparib were 58.9 % and 34.3% respectively. 
In Studies D0816C00004, D081BC00001 and D081BC00002, as anticipated based on t1/2 
values following single dose, systemic plasma exposure to olaparib (Cmax and AUC0-τ) 
following multiple dosing (100 mg to 300 mg tablet b.i.d.), was higher than after single 
dose administration. However, the observed mean accumulation ratio for AUC (RAUC = 
1.4-1.9) was more than expected as the temporal change parameter (TCP, AUC0-τ at steady 
state/AUC single dose) was more than unity, indicating that the PK of olaparib was time-
dependent. As olaparib is a substrate as well as a time dependent inhibitor of CYP3A, the 
mechanism of the time dependent change in olaparib PK is believed to be related to the 
above properties.  
In Study D0816C00007, the single dose PK was for 100 mg olaparib tablet, whereas the 
multiple dose PK was for 300 mg b.i.d.; therefore, a direct comparison of the single and 
multiple dose PK within each patient was not possible. However, following multiple daily 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 30 of 128 
 
b.i.d. dosing of olaparib (300 mg tablet), exposures (Cmax and AUC0-τ) were consistent with 
steady state exposures observed following multiple administration of the tablet (300 mg 
b.i.d.) under fasting conditions in Part B of the food effect study (D0816C00004). 
Similarly, steady state exposures (Cmax and AUC0-τ) in Study D081CC00001 (300 mg 
tablet) were also in the same range as those observed in Studies D0816C00007 and 
D0816C00004. 
In the Phase III study SOLO2 (D0816C00002) with sparse PK samples, steady state 
olaparib exposure parameters (area under the plasma concentration-time curve at steady 
state [AUCss], Cmax ss and Cmin ss) in ovarian cancer patients when dosed with tablet 
formulation at 300 mg b.i.d. were found to be in the same range as those in patients dosed 
with capsule formulation at 400 mg b.i.d. and were lower when compared with those in 
patients dosed with 300 mg b.i.d. tablet formulation in Phase I studies. There was a large 
variability in individual exposures among the studies and the low exposure observed in 
SOLO2 and OlympiAD may be a manifestation of a large between study variability. 
Although the mean exposure to olaparib in SOLO2 and OlympiAD studies was lower than 
the Phase I studies, there was a large overlap in individual patient exposures.  
The AUC for olaparib tablet across the clinical programme appears to increase 
approximately proportionally with dose.  
1.4.3.2. Metabolism and Excretion of Olaparib 
The metabolism and excretion of olaparib were investigated in 6 female patients (aged 34 
years to 72 years) following oral administration of a single 100 mg (~120 μCi) dose of 
olaparib in Study D0810C00010. Although 6 patients were dosed in total, only 5 received 
the intended 100 mg dose of olaparib (1 patient received only the 50 mg radiolabelled 
capsule). Recovery data were determined for all 6 patients but PK parameters were only 
reported for the 5 who received the full olaparib dose. 
Olaparib was the major component present in plasma and accounted for approximately 70% 
of the radioactivity present. Three other metabolites, M12, M15 and M18, each represented 
approximately 10% of the material (9.3%, 10.3% and 13.7%, respectively). These 
metabolites were identified as products of hydroxylation and opening of the cyclopropyl 
ring (M12), monooxygenation of the fluorophenyl ring (M15) and dehydrogenation of the 
piperazine ring (M18). The major drug derived components in plasma were M12 (ring-open 
piperazin-3-ol), M15 (4-fluorophenol (hydroxy)methyl) and M18 (piperazin 3-ol); each 
accounted for 9-14% of the plasma radioactivity. Drug-related material was eliminated in 
the urine (approximately 44% of the dose) and in the faeces (approximately 42% of the 
dose). 
In the urine, olaparib was the most abundant component, accounting for between 10% and 
19% of the dosed material. Up to 37 further drug-related components were observed. At 
least 20 components were observed in the pooled faecal samples with 6 components 
accounting for >1% of the dose and the remaining metabolites detectable only by 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 31 of 128 
 
HPLC/MS. The major components present were unchanged olaparib (0.6 to 14% of the 
dose) and M15 (0.9 to 8% of the dose). Four further metabolites (M9, M12, M23 and M25) 
were also prominent each accounting for ≤6% of the dose. 
1.4.3.3. Effect of Intrinsic Factors on the PK of Olaparib 
Following administration of oral doses to patients in the Japanese or Chinese tablet PK 
studies (D081BC00001 and D081BC00002, respectively) the Gmean Cmax and AUC 
observed in Japanese or Chinese patients were within the range observed for Western 
patients when given the same dose, 300 mg olaparib tablet. 
In the tablet population PK analysis, age, body weight and gender covariates were not 
found to be predictors of olaparib plasma exposure and therefore dose adjustment on the 
basis of age, body weight or gender is not required. 
The data obtained from the human mass balance study using the capsule formulation (Study 
D0810C00010) showed that both renal and metabolic routes were involved in the 
elimination of olaparib. 
A formal study to evaluate the impact of mild and moderate renal impairment on single 
dose olaparib tablet PK has been completed (D0816C00006). AUC increased by 24% and 
Cmax by 15% in patients with mild renal impairment (creatinine determined by Cockcroft 
Gault of 51 ml/min to 80 mL/min) and no olaparib tablet dose adjustment is required in this 
group. AUC and Cmax for olaparib were 44% and 26% higher in patients with moderate 
renal impairment, and a dose adjustment is recommended. Hence, it is recommended that 
patients must have creatinine clearance estimated using the Cockcroft-Gault equation of 
≥51 mL/min to be included in a clinical trial. If a patient develops moderate renal 
impairment whilst on treatment the recommended olaparib tablet dose is 200 mg b.d. (400 
mg total daily dose). It is not recommended that olaparib is dosed to patients with severely 
impaired renal function (creatinine clearance <30 ml/min) as data are not available in these 
patients. 
A formal study to evaluate the impact of hepatic impairment on olaparib tablet PK has been 
completed (Study D0816C00005). D0816C00005 is a 2-part study in patients with 
advanced solid tumours in which the PK of a single oral 300 mg tablet dose of olaparib is 
investigated in Part A and continued access to multiple dose olaparib (300 mg b.d.) is 
provided in Part B to obtain additional safety data. When olaparib (300 mg) was 
administered as a single dose to patients with mild hepatic impairment, there was a 13% 
increase in Geometric least squares (GLS) mean Cmax and a 15% increase in GLS mean 
AUC compared to those observed in patients with normal hepatic function. For patients 
with moderate hepatic impairment, there was a 13% decrease in GLS mean Cmax and an 
8% increase in GLS mean AUC compared to patients with normal hepatic function. The 
changes in AUC and Cmax in patients with mild and moderate hepatic impairment were 
small (15% or less) and were considered not clinically significant. There were also no 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 32 of 128 
 
obvious relationships for any of the PK parameters with any parameters associated with 
liver function, including serum bilirubin, albumin and prothrombin time.  
Olaparib is not recommended for use in patients with severe hepatic impairment as the 
safety and PK of olaparib has not been studied in these patients. 
The impact of previous gastric surgery on olaparib exposure when administered at 100 mg 
in combination with paclitaxel dosed weekly 80 mg/m2 was assessed in a subgroup of 
olaparib-treated dosed with advanced gastric cancer in Study D081BC00004. Exposure to 
olaparib in combination with paclitaxel appeared to be lower in patients with gastric 
surgery. 
1.4.3.4. Effect of Extrinsic Factors on the PK of Olaparib 
The effect of food on olaparib tablet has been investigated. Study D0816C00004 has 
formally evaluated the effect of food (a high fat meal) on the PK of olaparib following 
dosing of the tablet formulation to man. The point estimates for the treatment ratio for AUC 
and AUC from time zero to the last measurable concentration (AUC0-t) indicated a small 
(8%) increase in olaparib exposure when administered following a high fat meal which was 
of borderline statistical significance (treatment ratio: 1.08; 90% CI: 1.01-1.16). However, 
both the point estimate and 90% CI for the treatment ratios for AUC lay entirely within the 
0.80 to 1.25 bounds, indicating that there was no effect of food on olaparib AUC. In 
contrast, there was a statistically significant 21% decrease in Cmax following a high fat meal 
(treatment ratio: 0.79; 90% CI: 0.72-0.86). Co-administration with food slowed the rate of 
absorption (tmax delayed by 2.5 hours and Cmax reduced by 21%), however food did not 
significantly affect the extent of absorption (AUC), therefore olaparib tablet can be given 
without regard to food. 
Regarding drug-drug interactions: 
• 
CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance 
of olaparib. All clinical studies conducted to date have excluded co-administration of 
known strong inhibitors or inducers of CYP3A4/5. The data in Study D0816C00007 
indicated the presence of a marked interaction with a known strong inhibitor of 
CYP3A and P-glycoprotein (P-gp), itraconazole while the study D0816C00008 
indicated the presence of marked interaction with a known strong inducer of CYP3A 
and Pgp, rifampicin. It is therefore recommended that known strong inhibitors or 
inducers of CYP3A4/5 isozymes should be avoided with olaparib. 
Physiologically-based pharmacokinetic (PBPK) modeling has shown that moderate 
inhibitors will alter the clearance of olaparib and therefore concomitant use of 
moderate CYP3A inhibitors is not recommended with olaparib. It is also not 
recommended to consume grapefruit juice while on olaparib therapy.  
If a strong or moderate CYP3A inhibitor must be co-administered, the recommended 
olaparib dose reduction is to 100 mg b.i.d. (equivalent to a total daily dose of 200 
mg) with a strong CYP3A inhibitor or 150 mg b.i.d. (equivalent to a total daily dose 
of 300 mg) with a moderate CYP3A inhibitor. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 33 of 128 
 
PBPK modelling has shown that moderate CYP3A inducers will decrease olaparib 
AUC by approximately 50% and therefore concomitant use of moderate CYP3A 
inducers such as, but not limited to bosentan, efavirenz, etravirine, modafinil and 
nafcillin is not recommended with olaparib. If a moderate CYP3A inducer must be 
coadministered, the prescriber should be aware of a potential for decreased efficacy 
of olaparib. 
• 
In vitro olaparib is a substrate for the efflux transporter P-gp. Clinical studies to 
evaluate the impact of specific P-gp inhibitors and inducers have not been 
conducted; however based on the physical and absorption, distribution, metabolism 
and excretion properties of olaparib, there is low risk that P-gp modulator could 
significantly alter systemic exposure to olaparib. 
• 
A clinical study was conducted to evaluate the drug-drug interaction between 
olaparib and anti-hormonal agents. There was no drug-drug interaction between 
olaparib and letrozole or anastrozole. Tamoxifen (20 mg o.d.) decreased mean 
exposure to olaparib at steady state (by 20% for Cmax and by 27% for AUC0-12). In 
addition, olaparib had a small impact on exposure to tamoxifen (mean increase by 
13% for Cmax and 16% for AUC0-12). These were not considered to be clinically 
significant. Considering the small PK drug-drug interaction effects, the observed 
safety and tolerability profiles of olaparib when combined with anti-hormonal agents 
in this study, the known inter-patient variability for olaparib and the lack of 
relationship between olaparib plasma exposure and safety or efficacy, AstraZeneca 
recommend that olaparib can be given in combination with anti-hormonal agents 
without dose adjustment. 
• 
Substrates of UGT1A1 should also be given with caution in combination with 
olaparib (e.g., irinotecan, nintedanib, ezetimibe, raltegravir or buprenorphine). 
• 
Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro, with CYP2B6 being 
most likely to be induced to a clinically relevant extent. The potential for olaparib to 
induce CYP2C9, CYP2C19 and P-gp is unknown. It cannot be excluded that 
olaparib upon co-administration may reduce the exposure to substrates of these 
metabolic enzymes.Based on evaluation using enzyme activity, olaparib was not 
considered an inducer of CYP2C9 and 2C19. 
• 
In vitro, olaparib has been shown to be an inhibitor of P-gp, OATP1B1, OCT1, 
OCT2, OAT3, MATE1 and MATE2K and is a weak inhibitor of BRCP.  PBPK 
modelling predicts olaparib would have no effect on digoxin, a probe P-gp substrate. 
It cannot be excluded that olaparib may increase the exposure to substrates of 
OATP1B1 (e.g., bosentan, glibenclamide, repaglinide, statins and valsartan), OCT1 
(e.g., metformin), OCT2 (e.g., serum creatinine), OAT3, MATE1 and MATE2K. In 
particular, caution should be exercised if olaparib is administered in combination 
with any statin. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 34 of 128 
 
• 
Olaparib is predicted by PBPK modeling to be a weak inhibitor of CYP3A in vivo.  
Co-administration with olaparib is predicted to increase the AUC of CYP3A 
substrates such as midazolam and simvastatin by 60% or less.  This prediction is 
consistent with results from Study D081CC00001, in which olaparib was found to 
have only a small effect on the exposure of CYP3A substrates such as tamoxifen, 
anastrozole and letrozole. Based on in vitro data and PBPK modelling, caution is 
recommended when administering olaparib with sensitive CYP3A substrates or 
substrates with a narrow therapeutic margin (e.g. simvastatin, cisapride, 
cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and 
quetiapine). 
• 
In reference to interactions with chemotherapeutic agents PK sampling has been 
included in a number of studies evaluating the safety and tolerability of olaparib 
capsule when dosed in combination with a number of chemotherapeutic agents. The 
data available from these studies are summarised below. 
 
Table 2. Drug-drug interactions with chemotherapeutic agents 
Combinations (study codes) 
Results of the interaction analysis 
Olaparib capsule plus DTIC 
(Study D0810C00003) 
- Co-administration of DTIC had little or no effect on olaparib exposure 
and vice-versa. 
Olaparib capsule plus 
carboplatin, paclitaxel or 
carboplatin and paclitaxel 
(Studies D0810C00004 and 
D0810C00041) 
-  Although co-administration of carboplatin and paclitaxel has little or no 
effect on single dose exposure to olaparib, co-administration with 
paclitaxel does appear to reduce steady state exposure by up to 45%. 
- Co-administration with a single dose of olaparib appears to have had no 
effect on exposure to free carboplatin; 
- Co-administration with a single dose of olaparib appears to have had no 
effect on exposure to paclitaxel. 
Olaparib capsule + gemcitabine 
(Study D0810C00005) 
-  Co-administration of gemcitabine had no effect on steady state exposure 
to olaparib  
- Co-administration of olaparib had no effect on exposure to either 
gemcitabine or gemcitabine and 2',2'-difluorodeoxyuridine 
Olaparib capsule + topotecan 
(Study D0810C00006) 
- Olaparib steady state exposure was reduced when olaparib was dosed in 
combination with topotecan. The average reduction in exposure was 
approximately 20%. Due to bioanalytical difficulties, the impact of 
olaparib on exposure to topotecan could not be determined. 
Olaparib capsule + cisplatin 
(Study D0810C00021) 
- Co-administration of cisplatin had little/no effect on steady state exposure 
to olaparib 
Olaparib capsule + 
bevacizumab (Study 
D0810C00022) 
- Co-administration of bevacizumab did not affect steady state exposure to 
olaparib 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 35 of 128 
 
Olaparib + liposomal 
doxorubicin (Study 
D0810L00001) 
- A within patient comparison of the exposures achieved when olaparib 
was given in combination with liposomal doxorubicin showed that 
average olaparib Cmax and AUC from zero to 10 h was increased by 
approximately 30% and 40%, respectively. When further PK data, 
obtained only when dosed in combination with liposomal doxorubicin, 
were compared to data obtained following olaparib monotherapy in other 
studies, there was no clear difference in the olaparib exposures achieved. 
Based on comparison with literature values, there was no evidence that 
olaparib (at doses between 50 mg bd and 400 mg bd) altered the PK of 
liposomal doxorubicin. 
1.4.4. Effect of Olaparib on Cardiac Repolarisation 
Olaparib was active in the hERG assay at high concentrations but showed no evidence of 
effects on ECG intervals in anaesthetised dogs. The hERG assay IC50 (226 μM) was 60-
fold higher than the average steady state maximum free plasma concentration following a 
300 mg b.i.d. tablet dose in man (3.65 μM) suggesting that an effect of olaparib on QT 
interval in man is unlikely. 
The effect of olaparib on cardiac re-polarisation has been studied in Studies D0816C00004 
and D0816C00007. Triplicate, time matched digital ECGs were collected after both single 
and multiple dosing of olaparib in these studies and analysed by an independent 
cardiologist. The resulting data were subjected to statistical analysis. The primary aim of 
this analysis was to assess the effect of multiple doses of olaparib on the corrected QT 
interval using Fridericia’s formula (QTcF interval), by calculating the difference in Least 
Square (LS) means (olaparib QTcF interval LS mean at time t minus control QTcF interval 
LS mean at time t) and two-sided 90% CI. An analysis of covariance (ANCOVA) model 
was fitted to the pooled Part B data from Studies D0816C00004 and D0816C00007. In 
addition, supportive analysis was performed to investigate the effect of single dosing of 
olaparib on QTc. 
From this analysis of the pooled multiple dose data from Studies D0816C00004 and 
D0816C00007, the upper confidence limit of the two-sided 90% CI around the mean 
treatment effect was <10 ms for the contrast of multiple dose olaparib versus control for 
every time point, suggesting a lack of clinically relevant effect on cardiac repolarisation. 
The supportive single dose analysis also showed no effect of olaparib on cardiac 
polarisation. Olaparib had no clinically relevant effect on partial response (PR) and QRS 
interval or heart rate. 
In conclusion, these data have provided no indication of a clinically relevant effect on 
cardiac repolarisation (as detected by QT prolongation) following multiple doses of 300 mg 
b.i.d. of olaparib (tablet formulation) or following single doses of olaparib (tablet 
formulation). 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 36 of 128 
 
1.4.5. Clinical Experience 
Clinical experience with olaparib is fully described in the current version of the olaparib 
Investigator’s Brochure. 
The clinical development programme for olaparib continues to assess the effect of olaparib 
(as a single agent or in combination) in the treatment of patients with tumours enriched for 
HRD, including BRCA mutated cancers (germline and tumour). 
Olaparib has demonstrated anti-tumour activity in non-comparative studies in patients with 
gBRCA mutated cancers including ovarian, breast, pancreas and prostate. 
The capsule formulation of olaparib was registered for use in the European Union (EU) and 
United States (US) in December 2014 and has been approved in 28 other markets globally. 
The tablet formulation has subsequently been registered in the US in August 2017 and 
Japan in January 2018. The recommended olaparib monotherapy capsule dose is 400 mg 
b.i.d. Post marketing patient exposure for olaparib is estimated to be >6700 patient-years 
(6470 patient-years for capsules and 230 patient-years for tablets) up to 30 November 2017. 
The majority of completed studies have been performed with the capsule formulation of 
olaparib but, since 2012/2013 most new studies, including the Phase III registration studies, 
are being performed with the tablet formulation which delivers the therapeutic dose of 
olaparib in fewer dose units than the capsule.. The recommended olaparib monotherapy 
tablet dose is 300 mg b.i.d. 
Olaparib monotherapy (tablet formulation) is currently in Phase III investigation in patients 
with ovarian cancer and BRCA mutations, in patients with gBRCA mutated advanced breast 
cancer, in patients with gBRCA mutated breast cancer in the adjuvant treatment setting, in 
patients with gBRCA mutated advanced pancreatic cancer and in a combination treatment 
setting with paclitaxel in patients with advanced gastric cancer. Additionally, Phase I, II or 
III studies include investigation of cancers driven by other DNA homologous 
recombination repair deficiencies beyond BRCA mutations.  
As of 15 December 2017, approximately 8319 patients are estimated to have received 
olaparib in the clinical programme of Olaparib. Olaparib monotherapy is generally well 
tolerated at monotherapy doses up to 400 mg b.i.d. (capsule formulation) and 300 mg b.i.d. 
(tablet formulation) in patients with solid tumours. Adverse Event (AE) reports considered 
to be associated with administration of olaparib are generally mild or moderate (NCI-
CTCAE Grade 1 or 2) haematological effects (anaemia, neutropenia, lymphopenia, 
thrombocytopenia, leukopenia, mean corpuscular volume  [MCV] elevation and increase in 
blood creatinine), decreased appetite, nausea, vomiting, diarrhoea, dyspepsia, stomatitis, 
upper abdominal pain, dysgeusia, fatigue (including asthenia), headache dizziness and 
cough. Generally these AEs didn’t require treatment discontinuation. 
In a relatively small number of patients, pneumonitis, myelodysplastic syndrome (MDS) 
/acute myeloid leukaemia (AML) and new primary malignancies have been reported, 
however totality of data from the whole development programme does not support a 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 37 of 128 
 
conclusion that there is a causal relationship between olaparib and these events. These 
important potential risks for olaparib are being kept under close surveillance.  
The safety and efficacy data presented in this section consist of final report data. Only 
blinded serious adverse event (SAE) data are presented for the Phase III programme in 
ovarian cancer, breast cancer and gastric cancer as the studies are ongoing. 
In the majority of the completed studies providing efficacy and safety data to date, olaparib 
has been administered to patients via a GelucireTM capsule formulation. 
1.4.5.1. Olaparib Monotherapy Efficacy Data 
Data from three completed non-comparative Phase II studies provided efficacy data for 
olaparib (capsule) as a monotherapy in breast cancer and other solid tumours. Recently one 
completed, open label, controlled Phase III study has provided efficacy data for olaparib 
(tablet) as a monotherapy in breast cancer Descriptions of the study design and patient 
disposition/demography for each of these studies are provided in this section, followed by 
side by side presentations of Response Evaluation Criteria in Solid Tumours (RECIST) 
response and PFS data for the Phase II capsule studies, with special focus on data from 
breast cancer patients enrolled on those studies.  
• 
Study D0810C00002 (KU36-92): advanced solid tumours 
This was a first time in man (FTIM), Phase I, PK and biological evaluation of olaparib 
(capsule formulation) in patients with advanced tumours. The primary objective was to 
determine the safety, tolerability, dose-limiting toxicity (DLT), PARP inhibitory dose range 
and maximum tolerated dose (MTD) of olaparib in patients with advanced solid tumours. 
After the MTD was identified (400 mg b.i.d.), an expansion phase at 200 mg b.i.d. was 
opened in ovarian, breast and prostate cancer patients who had hereditary BRCA mutations. 
Overall, 98 patients were recruited and treated in the study. The main tumours by type were 
ovarian (54 [55.1%]), breast, (13 [13.3%]); large intestine (5 [5.1%]), prostate (4 [4.1%]) 
and skin cancers (4 [4.1%]). 
• 
Study D0810C00008 (KU36-44): gBRCA mutated breast cancer 
This was a Phase II, open-label, non-comparative, international, multicentre study to assess 
the efficacy and safety of olaparib (capsule formulation) given orally b.i.d. in patients with 
advanced gBRCA1 or gBRCA2 breast cancer. The primary objective was to assess the 
efficacy of the capsule formulation at 2 different doses of olaparib in terms of objective 
response rate (ORR) using RECIST in patients with advanced BRCA1 or BRCA2 related 
breast cancer. Patients received olaparib at a dose of 400 mg b.i.d. or 100 mg b.i.d. 
continuously in 28-day cycles, for multiple cycles until no further clinical benefit was 
apparent or the patient was withdrawn from the study. 
• 
Study D0810C00020: BRCA mutated or serous ovarian cancer, BRCA mutated 
or triple negative breast cancer (TNBC) 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 38 of 128 
 
This was a Phase II, open label, non-randomised correlative study to determine the ORR of 
single agent olaparib (400 mg b.i.d. capsule formulation) in patients with recurrent breast 
and ovarian cancer. The study enrolled both BRCA inherited mutation carriers and non-
carriers. Twenty-six patients with breast cancer were allocated to receive study treatment 
and all received at least one dose. The majority (69.2%) of patients with breast cancer were 
White with a mean age of 48.2 years (range 24 years to 80 years). 
• 
Study D0810C00042: advanced solid tumours in patients with a gBRCA 
mutation – non-ovarian cancer cohorts 
This was a Phase II, open-label, non-randomised, non-comparative, multicentre study to 
assess the efficacy and safety of olaparib (400 mg capsules) given orally b.i.d. in patients 
with advanced cancers who had a confirmed genetic BRCA1 and/or BRCA2 mutation. 
A total of 298 patients received treatment: 193 patients had ovarian cancer, 62 patients had 
breast cancer, 23 patients had pancreatic cancer, 8 patients had prostate cancer, and 12 
patients had other cancers. The mean age of the patients was 55.3 years (range 29 years to 
79 years). The majority of patients were White (283 [95%]) and female (272 [91.3%]). 
A summary of overall response (RECIST) in the non-ovarian cancer groups of studies 
D0810C00008, D0810C00020 and D0810C00042 is presented in Table 3 and median PFS, 
OS and response duration (RD) in the non-ovarian cancer groups of Studies D0810C00008, 
D0810C00020 and D0810C00042 is presented in Table 3. 
 
Table 3. Summary of overall response (RECIST) in Studies D0810C00008, D0810C00020 and 
D0810C00042 (non-ovarian cancer). 
 
Number (%) patients 
 
D0810C00008 
(gBRCA breast)a 
D0810C00020 
(breast)b 
Olaparib  
400 mg b.i.d 
D0810C00042 
(advanced gBRCA cancers)c 
Olaparib  
400 mg b.i.d 
Olaparib  
100 mg b.i.d 
Olaparib 
400 mg b.i.d 
N=27 
N=27 
N=26 
Breast 
N=62 
Pancreas 
N=23 
Prostate 
N=8 
Others 
N=12 
Objective 
response  
(CR + PR) 
6 (22.2) 
11 (40.7) 
0 
 
8 (12.9) 
5 (21.7) 
4 (50.0) 
1 (8.3) 
CR 
0 
1 (3.7) 
0 
0 
1 (4.3) 
0 
0 
PR 
6 (22.2) 
10 (37.0) 
0 
8 (12.9) 
4 (17.4) 
4 (50.0) 
1 (8.3) 
SD 
12 (44.4) 
12 (44.4) 
10 (38.5) 
29 (46.8) 
8 (34.8) 
2 (25.0) 
7 (58.3) 
PD 
9 (33.3) 
4 (14.8) 
15 (57.5) 
23 (37.1) 
9 (39.1) 
2 (25.0) 
3 (25.0) 
Not evaluable 
0 
0 
1 (3.8) 
2 (3.2) 
1 (4.3) 
0 
0 
a Data were based on the ITT population consisting of all enrolled patients who received at least one dose of 
olaparib irrespective of whether they completed the trial schedule and the study regime or not. 
b Data were based on the safety analysis set consisting of all patients who received at least one dose of olaparib. 
c Data were based on the full analysis set. 
b.i.d. Twice daily; CR Complete response; gBRCA Germline BRCA; ITT Intention-to-treat; PD Progressive 
disease; PR Partial response; RECIST Response Evaluation Criteria in Solid Tumours; SD Stable disease. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 39 of 128 
 
Table 4. Summary of median PFS, OS and DoR in Studies D0810C00008, D0810C00020 and 
D0810C00042 (non-ovarian cancer). 
 
D0810C00008 
(gBRCA breast)a 
D0810C00020 
(breast)b 
Olaparib  
400 mg b.i.d 
D0810C00042 
(advanced gBRCA cancers)c 
Olaparib 
400 mg b.i.d 
Olaparib  
100 mg b.i.d 
Olaparib  
400 mg b.i.d 
N=27 
N=27 
N=26 
Breast 
N=62 
Pancreas 
N=23 
Prostate 
N=8 
Median DoR 
(days) 
NR 
NR 
NC 
204.0 
134.0 
326.5 
Median PFS  
(95% CI) 
115.0 days 
(58-167) 
173.0 days 
(140-226) 
54.0 days 
(51-106) 
3.68 months 
(2.69-5.42) 
4.55 months 
(1.84-7.72) 
7.15 months 
(1.71-17.45) 
Median OS 
(months) 
NR 
NR 
NR 
11.01 
9.81 
18.38 
a Data were based on the ITT population consisting of all enrolled patients who received at least one dose of 
olaparib irrespective of whether they completed the trial schedule and the study regime or not. 
b Data were based on the safety analysis set consisting of all patients who received at least one dose of olaparib. 
c Data were based on the full analysis set. 
b.i.d. Twice daily; CI Confidence interval; DoR Duration of response (from onset of response); gBRCA 
Germline BRCA; ITT Intention-to-treat; NC Not calculable; NR Not reported; OS Overall survival; PFS 
Progression-free survival. 
 
• 
Study D0819C00003 (OlympiAD): gBRCA mutated breast cancer 
This was an open label, randomised study of olaparib versus standard Chemotherapy of 
Physician’s Choice (TPC) as treatment of MBC. Study patients harboured a deleterious 
germline mutation of BRCA1/2 (gBRCAm), were previously treated with an anthracycline 
and a taxane, and had received no more than 2 prior chemotherapy regimens for metastatic 
disease. Of the 302 patients who underwent randomisation, 205 were assigned to receive 
olaparib tablets 300 mg b.i.d. and 97 to receive TPC. 
Olaparib tablet monotherapy provided a statistically significant and clinically meaningful 
improvement in PFS compared with TPC. At 77% maturity, PFS by blinded independent 
central review was significantly longer in patients treated with olaparib versus TPC (HR 
0.58; 95% CI 0.43-0.80; p=0.0009; 7.0 vs. 4.2 months, respectively). Objective response rate 
was 59.9% and 28.8% in the olaparib and TPC arms, respectively. Final analysis of OS at 
64% maturity revealed no evidence of a detriment to survival in patients given olaparib 
compared to those given TPC, with a small non-significant numerical trend favouring 
olaparib. 
1.4.5.2. Olaparib 400 mg b.i.d. Monotherapy (capsule formulation) Pooled Safety Data 
This section presents a pooled analysis of olaparib 400 mg b.i.d. (capsule formulation) 
monotherapy safety data from Study D0810C00019 plus 11 additional studies. A total of 
766 patients with advanced solid tumours are included in this analysis. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 40 of 128 
 
In the olaparib 400 mg b.i.d. capsule pooled dataset, the contributing studies have differing 
patient populations. The majority of patients in the pooled dataset (522/766) had ovarian 
cancer. Patients with other advanced solid tumours, including breast (n=145), colorectal 
(n=42), pancreas (n=24) or prostate (n=8) cancers were also treated in these studies. With 
the exception of Study D0810C00019, where olaparib was administered in the maintenance 
setting to responding patients, the treatment setting was as a late line of therapy to patients 
with relapsed, progressive disease. 
The number of patients in the 400 mg b.i.d monotherapy pooled dataset who had at least 1 
AE in any category during the course of the study is 749 (97.8 %), any AE causally related 
to study treatment 666 (86.9 %), any AE of CTCAE grade 3 or higher 347 (45.3 %), and 
any AE leading to discontinuation of study treatment 45 (5.9%). Fatigue and anaemia were 
the most common CTCAE Grade 3/4 AEs in the capsule pool dataset: CTCAE Grade 3/4 
fatigue was reported by 6.9% of patients and CTCAE Grade 3/4 anaemia was reported by 
11.5% of patients. 
1.4.5.2. Olaparib 300 mg b.i.d. monotherapy (tablet formulation) pooled dataset 
This section presents a pooled analysis of olaparib 300 mg b.i.d. (tablet formulation) 
monotherapy safety data from Study D0816C00002 (including the China cohort) plus 10 
additional 
studies: 
D0819C00003 
(OlympiAD), 
D0810C00024, 
D0816C00004, 
D0816C00007, 
D0816C00008, 
D081BC00001, 
D081CC00001, 
D0816C00006, 
D0816C00005 and D081BC00002. A total of 759 patients with advanced solid tumours are 
included in this analysis.  
In the olaparib 300 mg b.i.d. tablet pool dataset, the contributing studies have differing 
patient populations. The majority of patients in the pooled dataset had either ovarian 
fallopian tube or primary peritoneal cancer (335/759) or breast cancer (268/759). Patients 
with other solid tumours including colon/colorectal (n=23), pancreas (n=12) or prostate 
(n=11) were also treated. Patients were generally heavily pre-treated with anticancer 
therapies. 
The number of patients in the 300 mg b.i.d. monotherapy tablet pool dataset who had at 
least 1 AE in any category during the course of the study is 741 (97.6 %), any AE causally 
related to study drug 654 (86.2 %), any AE of CTCAE Grade 3 or higher 278 (36. 6 %), and 
any AE leading to discontinuation of study treatment 50 (6.6%). 
Haematological toxicity was reported at an increased frequency with the tablet formulation, 
compared with the capsule formulation; however, anaemia and neutropenia remained 
manageable by interrupting or reducing the olaparib dose or giving blood transfusions or 
colony stimulating factor, when indicated; treatment discontinuation was rarely required. 
Reports of thrombocytopenia remained at low frequency with the tablet formulation; these 
events were primarily low grade and rarely required treatment discontinuation.  
Anaemia, neutropenia and fatigue were the most common CTCAE Grade 3/4 AEs in the 
tablet pool dataset: CTCAE Grade 3/4 anaemia was reported by 14.6% of patients, CTCAE 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 41 of 128 
 
Grade 3/4 neutropenia was reported by 3.8% of patients and CTCAE Grade 3/4 fatigue was 
reported by 3.2% of patients. 
AEs leading to discontinuation of olaparib occurred infrequently and were reported at a 
similar frequency in the tablet and capsule pooled datasets. Anaemia, leading to 
discontinuation was reported in a slightly higher proportion of patients in the tablet pool (7 
patients [1.5%]) compared with patients in the capsule pool (3 patients [0.4%]). The 
majority of deaths were reported as due to the disease under investigation, and for deaths 
unrelated to disease under study, there were no major differences between the capsule and 
tablet pooled datasets. 
1.4.5.3. Emerging Safety Profile 
This section lists those adverse drug reactions that are currently regarded as expected for 
regulatory reporting purposes. 
A full description of the emerging safety profile for olaparib, with guidance for 
Investigators, is provided in Section “Emerging Safety Profile” of the current version of the 
olaparib’s Investigator Brochure. 
Administration of olaparib monotherapy has been associated with adverse reactions (Table 
5), generally of mild or moderate severity (NCI-CTCAE Grade 1 or 2) and generally not 
requiring treatment discontinuation. The emerging safety profile for olaparib supports 
further studies in cancer patients. 
The safety profile is based on pooled data from 1248 patients treated with olaparib 
monotherapy in clinical trials in the therapeutic indication at the recommended dose.  
The following adverse reactions have been identified in completed clinical trials with 
patients receiving olaparib monotherapy where patient exposure is known. Adverse Drug 
Reactions are listed by Medical Dictionary for Regulatory Activities (MedDRA) SOC and 
then by MedDRA preferred term. Within each SOC, preferred terms are arranged 
bydecreasing frequency and then by decreasing seriousness. Frequencies of occurrence of 
adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); 
uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); and very rare (<1/10,000); 
not known (cannot be estimated from available data).. 
Table 5. Adverse Drug Reactions from Completed Clinical Studies 
 
 
Adverse reactions 
MedDRA System 
Organ Class 
 
 Frequency of all CTCAE grades 
Frequencya of CTCAE grade 3 and above 
Blood and 
lymphatic system 
disorders 
 
Very common 
Anaemiaa 
Common 
Very common 
Anaemiaa 
Common 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 42 of 128 
 
Neutropeniaa 
Thrombocytopeniaa 
Leukopeniaa 
Uncommon 
Lymphopenia 
Neutropeniaa 
Thrombocytopeniaa 
Leukopeniaa 
Uncommon 
Lymphopenia 
Immune system 
disorders 
 
Common  
Rasha 
Uncommon 
Hypersensitivitya,  
Dermatitisa 
- 
 
 
Metabolism and 
nutrition disorders 
 
Very common  
Decreased appetite 
Uncommon 
Decreased appetite 
Nervous system 
disorders 
 
Very common 
Dizziness  
Headache 
Dysgeusia 
Uncommon 
Dizziness  
Headache 
Respiratory, thoracic 
and mediastinal 
disorders 
 
Very common 
Cougha 
Uncommon 
Cougha 
Gastrointestinal 
disorders 
 
Very common 
Vomiting, 
Diarrhoea,  
Nausea, 
Dyspepsia  
Common 
Stomatitis 
Upper abdominal pain  
Common 
Vomiting, 
Diarrhoea,  
Nausea 
 
Uncommon 
Stomatitis 
Upper abdominal pain 
General disorders and 
administration site 
conditions 
 
Very common 
Fatigue (including asthenia) 
Common 
Fatigue (including asthenia) 
Investigations 
 
Common   
Increase in creatinine 
Uncommon 
Mean corpuscular volume elevationb 
 
Uncommon  
Increase in creatinine 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 43 of 128 
 
a Anaemia includes preferred terms (PTs) of anaemia, haemoglobin decreased, red blood cell count decreased, 
erythropenia and haematocrit decreased; Neutropenia includes PTs of neutropenia, granulocytopenia, 
granulocyte count decreased and neutrophil count decreased, febrile neutropenia, neutropenic infection and 
neutropenic sepsis; Thrombocytopenia includes PTs of thrombocytopenia, platelet count decreased, platelet 
production decreased and plateletcrit decreased; Leukopenia includes PTs of leukopenia and white blood cell 
count decreased; Cough includes PTs of cough and productive cough; Rash includes PTs of rash, rash 
erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, exfoliative rash 
and generalised erythema; Hypersensitivity includes PTs of hypersensitivity and drug hypersensitivity; 
Dermatitis includes PTs of dermatitis, dermatitis allergic and dermatitis exfoliative. 
b Represents the incidence of laboratory findings of elevations in mean corpuscular volume from baseline to 
above the upper limit of normal (ULN), not of reported adverse reactions. 
CIOMS Council for International Organizations of Medical Sciences; CTCAE Common Terminology Criteria 
for Adverse Events v.3.0; MedDRA Medical Dictionary for Regulatory Activities; SOC System organ class. 
 
A description of selected adverse reactions is included below: 
Haematological toxicity: Anaemia and other haematological toxicities are generally low 
grade (CTCAE Grade 1 or 2), however, there are reports of CTCAE Grade 3 and higher 
events. Anaemia was the most common CTCAE Grade ≥3 adverse reaction reported in 
clinical studies. Median time to  first onset of anaemia was approximately 4 weeks 
(approximately 7 weeks for CTCAE Grade ≥3 events). Anaemia was managed with dose 
interruptions and dose reductions, and where appropriate with blood transfusions. In 
clinical studies the incidences of dose interruptions, reductions and discontinuations for 
anaemia were 8.3%, 5.0% and 0.8%, respectively. An exposure-response relationship 
between olaparib and decreases in haemoglobin has been demonstrated. In clinical studies 
with olaparib, the incidence of CTCAE Grade ≥2 shifts (decreases) from baseline in 
haemoglobin was 20%, absolute neutrophils 15%, platelets 5%, lymphocytes 30% and 
leucocytes 20% (all % approximate). The incidence of elevations in MCV from low to 
normal at baseline to above the upper limit of normal was approximately 55%. Levels 
appeared to return to normal after treatment discontinuation and did not appear to have any 
clinical consequences. 
Baseline testing, followed by monthly monitoring of complete blood counts is 
recommended for the first 12 months of treatment with olaparib, and periodically after 
this time to monitor for clinically significant changes in any parameter during treatment 
which may require dose interruption or reduction and/or further treatment. 
Other laboratory findings: In clinical studies with olaparib the incidence of CTCAE 
Grade ≥2 shifts (elevations) from baseline in blood creatinine was approximately 15%. 
Data from a double-blind placebo controlled study showed median increase up to 23% from 
baseline remaining consistent over time and returning to baseline after treatment 
discontinuation, with no apparent clinical sequelae; 90% of patients had creatinine values of 
CTCAE Grade 0 at baseline and 10% were CTCAE Grade 1 at baseline. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 44 of 128 
 
Nausea and vomiting: Nausea was generally reported very early, with first onset within 
the first month of olaparib treatment in the majority of patients. Vomiting was reported 
early, with first onset within the first two months of olaparib treatment in the majority of 
patients. Both nausea and vomiting were reported to be intermittent for the majority of 
patients and can be managed by dose interruption, dose reduction and/or antiemetic 
therapy. Antiemetic prophylaxis is not required. 
Important potential risks of MDS/AML, pneumonitis and new primary malignancies are 
discussed in section 1.6.1. 
1.5. Study Rationale 
Approximately 15% of ovarian cancer patients and 5% of breast, pancreatic and prostate 
cancer patients have inherited mutations of BRCA1 or BRCA2. In addition to genetic loss of 
BRCA function, it has been suggested that a further ~20% of tumours display so-called 
“BRCAness”70,71 phenotype. Furthermore, reduced function of other key proteins in the 
homologous recombination pathway similarly results in increased sensitivity to PARP 
inhibition and enhancement of chemotherapy and radiotherapy treatments. For these 
reasons, PARP inhibition represents a novel approach to anti-tumour therapy and may 
address an unmet need in patients with BRCA associated cancer. 
1.6. Benefit/risk and ethical assessment 
As of 15 December 2016, approximately 6558patients with ovarian, breast, gastric, 
pancreatic, and a variety of other solid tumours are estimated to have received treatment 
with olaparib in AstraZeneca-sponsored, investigator-sponsored, and collaborative group 
studies and a Managed Access Programme. In the AstraZeneca-sponsored studies, olaparib 
has been given as either monotherapy (an estimated 2618patients) or in combination with 
chemotherapy or other anti- cancer agents (eg, capecitabine, vinorelbine, eribulin, 
abiraterone, topotecan, gemcitabine, carboplatin and paclitaxel, paclitaxel or liposomal 
doxorubicin), including studies where patients received monotherapy and combination 
therapy sequentially (n=1181)Of the 4475 patients treated with olaparib in AstraZeneca-
sponsored, interventional studies and the MAP, 2109 received the capsule formulation, 
2341 received the tablet formulation, and 25 received both capsule and tablet. . 
Approximately 1327patients have received comparator or placebo across the olaparib 
development programme in AstraZeneca-sponsored studies.  
From the available data to date, there is no evidence of any unexpected toxicity following 
long-term olaparib (capsule) monotherapy exposure. An analysis of monotherapy data 
across 12 AstraZeneca-sponsored monotherapy studies in 766 patients with ovarian cancer 
and other non-ovarian solid tumours who have been given olaparib capsules estimated that 
18.3% (140/766) of patients had been exposed to olaparib capsules for ≥12 months, 9.4% 
(84/1006) for >18 months,5.4% for >24 months, 3.3% for >36 months and 2.6% for >48 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 45 of 128 
 
months (as of 08 August 2016) at the time of database closure for the respective studies. 
Eighteen patients (2.1%) had received ≥60 months of olaparib exposure.   
The 300 mg b.i.d. monotherapy tablet regimen has shown an acceptable tolerability profile 
relative to the 400 mg b.i.d. capsule and has been determined to be the recommended 
olaparib monotherapy tablet dose for future studies with olaparib using the tablet 
formulation. Olaparib as monotherapy at doses up to 400 mg b.i.d. (capsule formulation) 
and 300 mg b.i.d. (tablet formulation) is generally well tolerated, with most common AEs 
including nausea, fatigue, vomiting, and anaemia, being mainly mild-to-moderate (CTCAE 
Grade ≤ 2) in severity. 
1.6.1. Important Potential Risks 
• 
Myelodysplastic syndrome (MDS) /acute myeloid leukaemia (AML) 
The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, 
including long-term survival follow-up, was <1.5 % and the majority of these events have 
had a fatal outcome. All patients had potential contributing factors for the development of 
MDS/AML, having received previous chemotherapy with platinum agents. Many had also 
received other DNA damaging agents. The majority of reports were in germline BRCA 
mutation carriers and some of the patients had a history of previous cancer or of bone 
marrow dysplasia. 
Since bone marrow is known to be a target organ for olaparib toxicity, increased risk of 
MDS/AML with long-term exposure to olaparib cannot be excluded. However, there is 
insufficient data at present to evaluate this relationship. Moreover, while non-clinical data 
suggest bone marrow progenitor cell populations are reduced temporarily following 
olaparib treatment, there is no evidence to date linking olaparib treatment to the generation 
of abnormal bone marrow precursors. Furthermore, all patients who developed MDS/AML 
had extensive prior chemotherapy and while it is not possible to exclude the contribution of 
olaparib, it must be considered that there were other potential contributing factors in all 
cases. The risk is perceived as low and not outweighing the potential benefit of study 
treatment in the breast cancer patients to be included in the current trial.  
Clinical guidelines for managing bone marrow toxicity are indicated in Section 5.4. Special 
Treatment Considerations. Dose Adjustments of Olaparib.  
• 
Pneumonitis 
Pneumonitis events have been reported in <1% of patients receiving olaparib monotherapy 
in clinical studies. The reports of pneumonitis had no consistent clinical pattern and were 
confounded by a number of pre-disposing factors (cancer and/or metastases in lungs, 
underlying pulmonary disease, smoking history, and/or previous chemotherapy and 
radiotherapy). When olaparib was used in clinical studies in combination with other 
therapies there have been events with a fatal outcome.   


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 46 of 128 
 
Investigation of any new or worsening pulmonary symptoms has been implemented as part 
of the safety management of the study in Section 5.4.2. Management of Non-
Haematological Toxicity. 
• 
New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other 
contributing factors/potential alternative explanations for the development of the new 
primary malignancy in all cases, including documented BRCA mutation, treatment with 
radiotherapy and extensive previous chemotherapy including carboplatin, taxanes, 
anthracyclines and other alkylating and DNA damaging agents.  
Study team will review emerging data from the trial in order to detect possible risks for the 
patients. 
To ensure robust safety monitoring of these adverse events of special interest (AESIs), 
patients enrolled on this clinical study will have safety assessments during the first week on 
study treatment on a monthly basis afterwards until treatment discontinuation for any 
reason, and in the follow up visit performed approximately 30 days after the last dose of the 
study treatment. Study monitors will be trained on the safety profile of olaparib and 
Investigators will be advised to consider a thorough follow up of those patients 
experiencing any AESI. Procedures for reporting AESIs are indicated in Section 6.2.3. In 
addition, a continuous data validation will be performed with periodic review of safety data 
by the GEICAM medical and pharmacovigilance department.  
1.6.2. Potential Benefit 
A Marketing Authorisation Application was approved in EU/EEA on 16 December 2014 
for the indication “LYNPARZA monotherapy for the maintenance treatment of adult 
patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high 
grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in 
response (complete response or partial response) to platinum-based chemotherapy”. 
A New Drug Application was approved in the US on 19 December 2014 for the indication 
”LYNPARZA monotherapy in patients with deleterious or suspected deleterious germline 
BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have 
been treated with three or more prior lines of chemotherapy”. The tablet formulation of 
olaparib was approved in August 2017 US for the maintenance treatment of adult patients 
with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a 
complete or partial response to platinum-based chemotherapy; and for the treatment of 
adult patients with deleterious or suspected deleterious germline breast cancer susceptibility 
gene (BRCA)-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 
or more prior lines of chemotherapy. 
Phase II clinical studies have investigated the effect of olaparib either as monotherapy or in 
combination with other chemotherapy agents in cancer patients. In patients carrying 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 47 of 128 
 
germline BRCA mutations, monotherapy studies in patients with heavily pre-treated breast 
cancer have reported an ORR of up to 41%, A phase 3 trial, OlympiAD showed that 
olaparib provided a significant benefit over standard therapy; median PFS was 2.8 months 
longer and the risk of disease progression or death was 42% lower with olaparib 
monotherapy than with standard therapy. 
US approved in January 2018 the tablet formulation for patients with deleterious or 
suspected deleterious gBRCAm, HER2-negative MBC who have previously been treated 
with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with 
hormone receptor (HR)-positive breast cancer should have been treated with a prior 
endocrine therapy or be considered inappropriate for endocrine treatment. Based on these 
results and data from the full clinical program to date, it is anticipated that olaparib will 
have a positive benefit risk profile for the treatment of the small well-defined population of 
advanced triple negative breast cancer patients with promoter methylation of BRCA. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 48 of 128 
 
2. Objectives 
2.1. Primary Objective 
• To analyse the olaparib efficacy in the treatment of patients diagnosed of 
advanced triple negative breast cancer (TNBC) with BRCA1 and/or BRCA2 
promoter methylation assessed in somatic DNA. 
  
2.2. Primary End-point 
• Objective Response Rate (ORR) defined as Complete Response (CR) plus Partial 
Response (PR) according to Response Evaluation Criteria in Solid Tumours 
(RECIST) version 1.1.  
2.3. Secondary Objectives 
• To analyse other efficacy measures. 
• To analyse olaparib safety. 
• To explore changes in the methylation status of BRCA1/2 promoter in germline 
DNA prior and after treatment discontinuation for any reason and correlate 
germline BRCA1/2 methylation data with efficacy parameters. 
• To correlate BRCA1/2 methylation between germline and somatic DNA and 
between primary tumour and metastatic lesions.  
• To correlate BRCA1/2 expression with methylation status of BRCA1/2 promoter 
and efficacy parameters.  
2.4. Secondary End-points 
• Clinical Benefit Rate (CBR), Response Duration (RD), Progression Free 
Survival (PFS) and Overall Survival (OS). 
• Adverse events defined by the NCI-CTCAE (National Cancer Institute Common 
Terminology Criteria for Adverse Events) version 4.0. 
• The methylation status of BRCA 1 and 2 promoters will be measured in germline 
DNA from blood cells at the beginning of the study and after disease 
progression, or at the end of study treatment by other reason, and in paired 
primary and metastatic lesions. It will be analysed: 1) changes of germline 
methylation pre and post-treatment; 2) correlation between germline methylation 
status and efficacy outcome data; 3) correlation between germline and somatic 
methylation status and 4) correlation between primary and metastatic lesions.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 49 of 128 
 
• mRNA levels of BRCA1 and 2 will be assessed in blood and available tumour 
samples. Expression data will be correlated with promoter methylation status of 
BRCA and outcome data.   
2.5. Exploratory Objectives 
•  To explore biomarkers of clinical activity in tumour and blood samples.  
2.6. Exploratory End-points  
• Biomarker values from the primary or metastatic tumour tissue could be used for 
assessment of biomarkers related to breast tumour sensitivity and/or resistance to 
olaparib (e.g. may include but not limited to somatic BRCA1/2 mutational status 
or other genes related to cancer susceptibility or thought to be related to the drug 
mechanism of action). These samples will be instrumental to explore biomarkers 
of response or resistance to olaparib.  
• DNA and RNA obtained from the blood samples collected during the study may 
be used for potential pharmacogenomics analyses related to drug response or 
adverse drug reactions (including but not limited to comparison of germline 
DNA or RNA patterns of patients who respond well and those who respond 
poorly to treatment). For example, genes coding drug metabolizing enzymes, 
drug transport proteins or genes involved in DNA repair pathways, cancer 
susceptibility or thought to be related to the drug mechanisms of action may be 
analysed.  
• Specific mutations or epigenetic biomarkers identified in pre-therapy tumour 
specimens as potentially linked to treatment response could be tested in plasma 
DNA. A targeted NGS panel may be designed to study all the candidate 
mutations. Plasma DNA has also the potential to be a surrogate of tumour load 
and may also be instrumental to monitor disease. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 50 of 128 
 
3. Investigational Plan 
3.1. Study Design 
This is a multicenter, non-randomized, phase II clinical trial to assess the efficacy and 
safety of olaparib in monotherapy in patients diagnosed of advanced triple negative BC 
with methylation of BRCA1 and/or 2 promoters (assessed in DNA from metastatic lesions) 
and absence of BRCA1 and 2 germline mutations. Patients must have received at least one 
previous regimen in the advance disease setting.  
Figure 1 Study Design 
 
 
Potential eligible patients will be screened to assess germinal (g) BRCA mutational status at 
Myriad laboratory (unless the BRCA mutational status is already known based on a Myriad 
previous report).  
Blood samples for mutational BRCA screening could be sent either 1) during the previous 
line of treatment, once the eligibility criteria have been reviewed and the patient is 
considered a potential candidate for the study (at least the patient must have measurable and 
biopsiable disease) or 2) after end of the line of treatment prior to study enrolment 
(simultaneously to the shipment of the tumour samples for methylation analysis). A specific 
ICF must be signed for this screening assessment. 
Somatic (s) BRCA promoter methylation will be assessed also centrally at an external 
reference central laboratory selected by GEICAM. Tumour samples must proceed from a 
metastatic lesion, it is strongly recommended to obtain it after the line treatment 
immediately previous to the study entry. 
Patients with a positive methylation status on BRCA1 and/or BRCA2 and lacking of 
known deleterious or suspected deleterious mutations in both genes could be included in 
the study to receive olaparib tablet formulation at 600 mg daily dose (given in two oral 
administrations of 300 mg every 12 hours approximately). Blood and tumour samples 
collected from all registered patients could be used for the secondary and exploratory 
analysis of the study, including but not limited to the assessment of germline methylation 
status and gene expression levels of BRCA1/2. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 51 of 128 
 
Patients will continue to receive their treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, 
whichever occurs first.  
Each assessment of tumour response will be performed as scheduled according to the 
calendar regardless of any dosing delay to prevent the introduction of bias into the 
assessment of efficacy.  
According to RECIST v.1.1 in case of patients with a global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease progression at 
that time every effort should be made to document objective progression, even after 
discontinuation of treatment. The objective response status of such patients should be 
determined considering RECIST v.1.1 instructions. In case any efficacy assessment cannot 
be done, they will be considered not evaluable for response rate analysis and PFS will be 
censored at the date of the last tumour assessment.  
3.1.1. Step 1 analysis of the optimal two stage Simon model 
Following the two-stage Simon design, it will review that 4 of the first 12 evaluable 
patients show tumour response according to RECIST v.1.1, additional patients will be 
included to get a total of 34 patients. 
3.2. Duration of the Study  
It is estimated that the patient recruitment will be completed approximately in 24 months.  
All patients included will receive study therapy until radiographic or symptomatic 
progression, unacceptable toxicity or withdraw of the informed consent, whatever occurs 
first, this is the active treatment phase. Patients discontinuing the study treatment will enter 
the follow-up phase.  
For safety reasons all patients will have a visit 30 (+/-7) days after finishing treatment with 
the study drugs/medications. This post-treatment visit must be performed before starting 
with any new anticancer therapy; however, in case the beginning of this new therapy cannot 
be delayed as per the investigator’s judgment, the safety visit may be performed in advance, 
but always before starting with the new anticancer therapy. 
All patients will be followed till death or data cut-off date to evaluate the OS objective.  
The start date of study is the date of the first site initiation visit. The data cut-off date will 
be the date of last patient´s death or withdraw of the informed consent or the date when 
there is sufficient data to achieve the primary and secondary objectives, whichever comes 
first. It is estimated that the final analysis could be performed approximately 30 months 
after the enrolment of the first patient because, considering a median OS of 12 months, it is 
estimated that more than 50% of death events will have occurred at that time and overall 
survival analysis could be performed. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 52 of 128 
 
The study will be considered complete following the data cut-off date and data-lock for the 
final analysis. Performing exploratory objectives will be independent of the date of the end 
of the study. 
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 53 of 128 
 
4. Study Population 
4.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following 
criteria. Any asterisked* are also applicable as an inclusion criteria prior to perform the 
BRCA methylation testing via central testing; to perform the BRCA methylation test, 
investigator judgement of patient’s potential eligibility to the study should be assessed as 
per Protocol Attachment 1. Study Schedule and by reviewing the below inclusion 
criteria):  
1. *The patient has signed and dated the informed consent document and it has been 
obtained before conducting any procedure specifically for the study. 
2. Female ≥ 18 years of age on day of signing informed consent. 
3. Patient with histological confirmation of breast cancer with evidence of advanced 
disease not amenable to resection or radiation therapy with curative intent.  
4. Documented triple negative disease by immunohistochemistry (IHC) and/or in situ 
hybridization based on local testing (preferably assessed on the most recent tumour 
biopsy available). TN is defined as negative hormone receptor status (< 1% of 
tumour cells with ER and PgR expression) and HER2-negative status (defined as 
IHC score 0/1+ or negative by in situ hybridization according to local criteria).  
5. Patient must have received at least one previous regimen in the advance disease 
setting. 
6. Absence of deleterious or suspected deleterious germline mutations in BRCA1 and 
BRCA2. Germinal BRCA mutational status will be centrally assessed in Myriad 
laboratories to check eligibility unless the test has been previously performed at 
Myriad and absence of mutations has been determined. 
7. Availability of a tumour tissue sample from the metastatic lesions (every effort 
should be done to obtain the sample after the previous therapeutic regimen for 
advanced disease) for central testing. 
8. Documented methylation of BRCA1 and/or 2 promoters based on central testing by 
analysis on the most recent tumour from metastatic lesions available. 
9. At least one lesion measurable not previously irradiated, that can be accurately 
measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes 
which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) or clinical examination and which is suitable for accurate 
repeated measurements according to RECIST v.1.1.  
10. Patients must have normal organ and bone marrow function measured within 28 
days prior to administration of study treatment as defined below: 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 54 of 128 
 
• Haemoglobin ≥ 10.0 g/dL with no blood transfusions in the past 28 days 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
• Platelet count ≥ 100 x 109/L 
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
• 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 ≤ 5 x ULN 
• Patients must have creatinine clearance estimated using the Cockcroft-Gault 
equation of ≥ 51 mL/min: 
Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a 
                             
    serum creatinine (mg/dL) x 72 
a where F=0.85 for females. 
11. *Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (see 
protocol attachment 2). 
12. *Patient must have a life expectancy ≥ 16 weeks. 
13. *Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential: negative urine or serum pregnancy test within 28 days of study treatment 
and confirmed prior to treatment on day 1. 
Postmenopausal patient is defined as a woman fulfilling any one of the following 
criteria (based on the NCCN definition of menopause [National Comprehensive 
Cancer Network 2008]): 
• 
Prior bilateral oophorectomy. 
• 
Age > 60 years. 
• 
Age ≤ 60 years and with amenorrhea for 12 or more months in the absence 
of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle 
stimulating hormone and estradiol in the postmenopausal range.  
14. Olaparib is regarded as a compound with medium/high foetal risk, patients of 
childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination as listed below. 
This should be started from the signing of the informed consent and continue 
throughout period of taking study treatment and for at least 1 month after last dose 
of study drug or they must totally/truly abstain from any form of sexual intercourse 
(see below).  
Acceptable non-hormonal birth control methods include:  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 55 of 128 
 
- Total sexual abstinence. Abstinence must continue for the total duration of the 
study treatment and for at least 1 month after one dose. Periodic abstinence 
(e.g., calendar ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
- Vasectomised sexual partner PLUS male condom. With participant assurance 
that partner received post-vasectomy confirmation of azoospermia. 
- Tubal occlusion PLUS male condom. 
- Intrauterine Device (IUD) PLUS male condom. Provided coils are copper-
banded. 
Acceptable hormonal methods: 
- Normal and low dose combined oral pills PLUS male condom. 
- Cerazette (desogestrel) plus male condom with spermicide. Cerazette is 
currently the only highly efficacious progesterone based pill. 
- Hormonal shot or injection (eg., Depo-Provera) PLUS male condom.  
- Etonogestrel implants (e.g. Implanon or Norplan) PLUS male condom. 
- Norelgestromin/ethinyl estradiol (EE) transdermal system PLUS male condom 
- Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS-Mirena®) 
PLUS male condom. 
- Intravaginal device PLUS male condom (e.g. EE and etonogestrel). 
14. *Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits, laboratory tests and examinations 
and other study procedures. 
4.2. Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria. Any 
asterisked* are also applicable as an exclusion criteria prior to perform the BRCA 
methylation testing via central testing; to perform the BRCA methylation test, investigator 
judgement of patient’s potential eligibility to the study should be assessed as per Protocol  
Attachment 1. Study Schedule and by reviewing the below exclusion criteria): 
1. Involvement in the planning and/or conduct of the study (applies to the sponsor and/or 
study site staff). 
2. Previous enrolment in the present study.  
3. Participation in another clinical study with an investigational product during the last 4 
weeks. 
4. *Any previous treatment with a PARP inhibitor, including olaparib.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 56 of 128 
 
5. *Patients with other malignancy within the last 5 years, except: adequately treated non-
melanoma skin cancer (basal cell or squamous cell carcinoma), curatively treated in-
situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial 
carcinoma, or other solid tumours including lymphomas (without bone marrow 
involvement) curatively treated with no evidence of disease for ≥ 5 years prior to study 
inclusion. Patients with a history of localised breast cancer with a tumour histology 
different to TN, with no evidence of disease for ≥ 5 years since they completed their 
adjuvant treatment. 
6. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons), within 3 weeks prior to study treatment (or a longer period depending on the 
defined characteristics of the agents used).  
7. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period 
or family history of long QT syndrome. 
8. *Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting olaparib is 2 weeks. Please refer to section 5.5.2.1 about strong 
and moderate CYP3A inhibitors.   
9. *Concomitant use of known strong (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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3 
weeks for other agents. Please refer to section 5.5.2.2 about strong and moderate 
CYP3A inducers.   
10. *Persistent toxicities (> NCI-CTCAE grade 2) caused by previous cancer therapy 
(except alopecia or other toxicities not considered a safety risk for the patient at 
investigator´s discretion). 
11. *Patients with myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) or 
with features suggestive of MDS/AML.  
12. *Patients with symptomatic uncontrolled brain metastases. A scan to confirm the 
absence of brain metastases is not required. Patients with brain metastases may be 
eligible for the study only if more than 4 weeks from treatment completion for these 
metastases (including radiation and/or surgery), are clinically stable at the time of 
study entry. 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. Patients with 
spinal cord compression unless considered to have received definitive treatment for 
this and evidence of clinically stable disease for 28 days.    


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 57 of 128 
 
13. Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
14. *Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
15. *Breast feeding women.  
16. *Immunocompromised patients, e.g. patients who are known to be serologically 
positive for human immunodeficiency virus (HIV).  
17. *Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting 
the infection through blood or other body fluids. 
18. *Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product.  
19. *Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection or laboratory 
abnormality that may increase the risk associated with study participation or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study. 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, severe hepatic impairment (according 
to Child-Pugh classification), an extensive interstitial bilateral lung disease on High 
Resolution Computed Tomography (HRCT) or any psychiatric disorder that prohibits 
obtaining informed consent.  
20. *Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
21. *Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria 
nº10). 
Procedures for withdrawal of incorrectly enrolled subjects see Section 4.4.Discontinuations. 
4.3. Restrictions during the Study 
It is not recommended to consume grapefruit juice while on olaparib therapy. 
Consider information about contraception in section 4.1. Inclusion Criteria.  
Consider information about restricted concomitant medication in section 5.5. General 
Concomitant Medication and Supportive Care Guidelines.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 58 of 128 
 
4.4. Discontinuations 
4.4.1. Discontinuation of Study Drugs/Medications 
The criteria for enrolment must be followed explicitly. If a patient who does not meet 
enrolment criteria is inadvertently enrolled, that patient should be discontinued from the 
study drugs/medications, but can be allowed to continue in the study in order to provide the 
follow-up data needed for the analysis of the entire population. An exception may be 
granted if the patient, in the opinion of the Investigator, is having benefit from the study 
drugs/medications. In these rare cases, the investigator must obtain documented approval 
from GEICAM to allow the patient to continue to receive the study drugs/medications. 
Patients can be discontinued from the study therapy in the following circumstances: 
• Patient’s own request. The patient is at any time free to discontinue treatment, 
without prejudice to further treatment. 
• Unacceptable toxicity as defined in the protocol. 
• Any clinical adverse event (AE), laboratory abnormality or inter-current illness 
which, in the opinion of the investigator, indicates that continued participation in the 
study is not in the best interest of the patient. 
• Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute 
myeloid leukaemia (AML)  
• Pregnancy: 
✓ Instruct to contact the investigator or study staff immediately if they suspect 
they might be pregnant. 
✓ The investigator must immediately notify GEICAM if a study patient becomes 
pregnant. 
• Tumour progression as defined in the protocol. 
• Severe non-compliance with the study protocol by the patient 
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g. infectious disease) 
illness. 
• Physician’s decision, including need of other anti-cancer therapy, not specified in the 
protocol.  
• Termination of the study by GEICAM. 
All permanent treatment discontinuation should be recorded by the Investigator in the 
eCRF when considered as confirmed. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 59 of 128 
 
It is important to discriminate between discontinuation of study treatment only and 
withdrawal from study (study treatment and follow up). 
4.4.2. Discontinuation of Study Sites 
Study Site participation may be discontinued if GEICAM, the investigator or the 
Independent Ethics Committee (IEC) of the study site judges it necessary for any reason.  
4.4.3. Discontinuation of Study 
The study may be discontinued by GEICAM if this is medically reasonable and consistent 
with applicable regulations of Good Clinical Practice (GCP). Stopping the study for 
medical reasons may be required if patients experienced adverse reactions under the 
treatment with the study drug/medication or if new information about the safety or 
effectiveness of the study drug/medication justifies it.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 60 of 128 
 
5. Treatment 
5.1. Treatments Administered 
Patients will receive the following treatment: 
Olaparib as single agent at a continuous daily dose of 600 mg (tablet formulation), given in 
two oral administrations of 300 mg with a dosing interval of about 12 h with a window 
interval of 2 hours before and after the scheduled time.  
Olaparib is for oral use. Olaparib tablets should be taken with one glass of water and 
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 patient 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 patient 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 patient should take their 
allotted dose at the next scheduled time.  
The treatment discontinuation criteria are indicated in Sections 3.2 and 4.4.1. 
5.2. Materials and Supplies 
5.2.1. Doses and treatment regimens 
For this study, the term “study drug/medication” (Investigational Medicinal Product [IMP]) 
refers to olaparib. 
The AstraZeneca Pharmaceutical Development R&D Supply Chain will supply olaparib to 
GEICAM as as round or oval green film-coated tablet containing 100 mg or 150 mg of 
olaparib.  
Table 6. Product Descriptions 
IMP 
Dosage form and strength 
Olaparib 
100 mg tablet 
Olaparib 
150 mg tablet 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
GEICAM will provide the study sites with olaparib for the purpose of this study.  
For all centres, olaparib tablets will be packed in high-density polyethylene (HDPE) bottles 
with child-resistant closures. Each dosing container will contain required sufficient 
medication for at least 28 days plus overage. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 61 of 128 
 
Olaparib will be dispensed to patients prior to initiate cycle 1 and every 28 days (+/- 7 
days) thereafter until the patient completes the study, withdraws from the study or closure 
of the study.  
For guidance on dose reductions for management of AEs refer to section 5.4. Special 
Treatment Considerations. Dose Adjustments of Olaparib. 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided see section 5.5.2. Restricted concomitant medications. 
5.2.2. Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. 
Label text will be translated into local language.  
Each bottle of olaparib will have an investigational product label permanently affixed to the 
outside stating that the material is for clinical trial/investigational use only and should be 
kept out of reach and sight of children. The label will include the dosing instructions and a 
space for the enrolment code (E-code) to be completed at the time of dispensing. 
The label will include the following information: 
• blank lines for quantity of tablets to be taken 
• enrolment code (E-code) 
• date of dispensing 
• instructions stating that the olaparib tablets should be taken at approximately the 
same time each morning and evening 
5.2.3. Storage  
Storage conditions stated in the Study Reference Safety Document may be superseded by 
the label storage. 
Olaparib should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements under appropriate storage conditions. Olaparib should 
be stored at at the study site at controlled room temperature in their original container. The 
label on the bottle specifies the appropriate storage.  
Investigators and site staff are reminded to continuously monitor room storage temperatures 
and ensure that thermometers are working correctly as required for proper storage of the 
investigational product. These include thermometers for the room storage. Any temperature 
excursions must be reported immediately to GEICAM and documented. Once a deviation is 
identified, the investigational product MUST be quarantined and not used until GEICAM 
provides documentation of permission to use the investigational product.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 62 of 128 
 
Returned medication should be stored separately from medication that needs to be 
dispensed.  
5.2.4. Accountability 
It is the responsibility of the investigator to ensure that a current record of olaparib 
disposition is maintained at each study site where the study drug is inventoried and 
disposed. Records or logs must comply with applicable regulations and guidelines. 
On a per-patient basis, records must be maintained documenting dates and quantities (ie, 
pill counts) of provided study treatment dispensed and returned at each study visit. 
GEICAM will provide forms to facilitate inventory control if the staff at the investigational 
site does not have an established system that meets these requirements. 
During the course of the study, the monitor regularly will review the records of medication 
stocks and document preservation ensuring it is properly performed according to ICH-GCP.  
After each monitoring visit, the study drug and containers returned by the patients and upon 
completion or termination of the study, all unused and/or partially used study drug will be 
preferably destroyed at the site per institutional policy, the site must obtain written 
authorization from the Sponsor before it is destroyed, and this destruction must be 
documented on the appropriate form. It is the investigator´s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept.  
5.3. Method of Assigning a Patient to a Treatment 
Patients will be screened by one of the Investigators prior to entry on this study. An 
explanation of the study and discussion of the expected side effects and presentation of the 
informed consent document/s will take place. Eligible and consenting patients (entered) 
will be registered into the study.  
To check eligibility, a blood sample must be sent to Myriad laboratory to assess the 
existence of germinal BCRA mutations (unless the BRCA mutational status is already 
known based on a Myriad previous report) and tumour samples must be sent to the central 
pathology laboratory, where it will be obtained DNA that will be sent to the central 
epigenetics laboratory for assessment of methylation status of BRCA1 and 2. . Patients with 
a positive methylation status of either BRCA1 or 2 genes and lacking of gBRCA mutations 
in both genes could be enrolled in the study and receive the Study treatment, although 
blood and tumour samples collected from all registered patients could be used for the 
secondary and exploratory objectives of the study. Instructions for timing and procedures to 
be followed for sample shipment are indicated in section 6.3 and Protocol Attachment1 of 
the protocol.   


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 63 of 128 
 
No patients can receive protocol treatment until registration and enrolment has been 
performed. All eligibility criteria must be met at the time of enrolment. There will be no 
exceptions. Any question should be addressed with GEICAM prior to registration or 
enrolment. The eligibility checklist must be completed and signed by the Principal 
Investigator or Sub-Investigator prior to enrolment and it should be filed with the study 
documentation. Inclusion and exclusion criteria needed to be assessed prior to the shipment 
of samples for BRCA analysis are indicated in section 4. Study Population. 
The study personnel at the site will register and enrol the patient through the eCRF and the 
system will send the unique number of the patient identification to the site.   
All eligible patients registered in the study will be entered in a patient screening log 
maintained by each site and the GEICAM central office. Only after the confirmation of the 
enrollment by the system, the patient can receive the study treatments. All patients enrolled 
in the study will be registered in a Patient Enrollment and Identification Log and will be 
only maintained by the site. 
Trial treatment must be administered within 7 days from enrolment.  
5.4. Special Treatment Considerations. Dose Adjustments of Olaparib 
All dose modifications should be based on the worst preceding toxicity.  
Every effort should be made to administer study treatment at the planned dose and 
schedule. However, in the event of significant treatment-related toxicity, administration of 
olaparib may need to be adjusted as described in the following sections. Depending on the 
nature of the toxicity observed, dose adjustments may be required for olaparib.  
In the event of significant treatment-related toxicity, olaparib dosing may be interrupted 
and/or reduced. Patients are to be instructed to notify Investigators at the first occurrence of 
any adverse sign or symptom. 
All dose modifications/adjustments must be clearly documented in the patient's source 
notes and the appropriate section of the eCRF.  
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 4 weeks on each occasion. If the interruption is any longer, the 
GEICAM study team must 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 reduction is allowed and study treatment 
should be discontinued. 
Once dose is reduced, escalation is not permitted. 
Olaparib recommended dose modifications for treatment related toxicities requiring 
treatment interruption/reduction or persisting despite optimal medical treatment are 
described in the following sections. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 64 of 128 
 
5.4.1. Management of haematological toxicity 
5.4.1.1. Management of Anaemia 
Table 7. Management of anaemia 
Common treatable causes of anaemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be excluded. In some cases management of anaemia may require 
blood transfusions. For cases where patients develop prolonged haematological toxicity (≥2 
week interruption/delay in study treatment due to NCI-CTCAE grade 3 or worse anaemia 
and/or development of blood transfusion dependence), refer to Section 5.4.1.3. 
Management of Prolonged Haematological Toxicities while on Study Treatment5.4.1.3. 
Management of Prolonged Haematological Toxicities while on Study Treatment.   
5.4.1.2. Management of Neutropenia, Leukopenia and Thrombocytopenia 
Table 8. Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
NCI-CTCAE  
Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this should 
be for a maximum of 4 weeks; appropriate supportive treatment and causality 
investigation. 
NCI-CTCAE  
Grade 3-4 
Dose interruption until recovered to NCI-CTCAE grade 1 or better for a 
maximum of 4 weeks. If repeat 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. 
Haemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(NCI-CTCAE 
Grade 2) 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive treatment 
(e.g. transfusion) or interrupt dose for a maximum of 4 weeks.  
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb 
≥ 10 g/dl and upon recovery dose reduction to 250 mg twice daily as a 
first step and to 200 mg twice daily as a second step may be considered. 
Hb < 8 g/dl 
(NCI-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 ≥ 10 
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. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 65 of 128 
 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by 
the Investigator with close follow up and interruption of study drug if CTC grade 3 or 
worse neutropenia occurs.  
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local 
hospital guidelines. Please note that G-CSF should not be used within at least 24 h (7 days 
for pegylated G-CSF) of the last dose of study treatment unless absolutely necessary.  
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
For cases where patients develop prolonged haematological toxicity (≥ 2 week 
interruption/delay in study treatment due to CTC grade 3 or worse), refer to Section 5.4.1.3. 
Management of Prolonged Haematological Toxicities while on Study Treatment. 
5.4.1.3. Management of Prolonged Haematological Toxicities while on Study Treatment 
If a patient develops prolonged haematological toxicity such as: 
• ≥ 2 week interruption/delay in study treatment due to CTC grade 3 or worse 
anaemia and/or development of blood transfusion dependence 
• ≥ 2 week interruption/delay in study treatment due to CTC grade 3 or worse 
neutropenia (ANC < 1 x 109/L) 
• ≥ 2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
< 50 x 109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear.  
If any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to haematologist for further investigations. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
haematological practice. Study treatment should be discontinued if blood counts do not 
recover to CTC grade 1 or better within 4 weeks of dose interruption. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder 
should be reported as an SAE and full reports must be provided by the Investigator to 
GEICAM. Olaparib should be discontinued if patient’s diagnosis of MDS and/or AML is 
confirmed.   
5.4.2. Management of Non-Haematological 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 study monitor must be informed.  
Where toxicity reoccurs following re-challenge with study treatment, and where further 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 66 of 128 
 
dose interruptions are considered inadequate for management of toxicity, then the patient 
should be considered for dose reduction or must permanently discontinue study treatment. 
Olaparib can be dose reduced to 250 mg b.i.d. as a first step and to 200 mg b.i.d. as a 
second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event 
occurs which the investigator considers to be related to administration of study treatment. 
5.4.2.1. Management of New or Worsening Pulmonary Symptoms 
 If new or worsening pulmonary symptoms (e.g. dyspnoea) or radiological abnormalities 
occur in the absence of a clear diagnosis, an interruption in study treatment 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 treatment can be restarted, if deemed appropriate by the 
Investigator. If significant pulmonary abnormalities are identified, these need to be 
discussed with GEICAM.   
5.4.2.2. Management of Nausea and Vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients 
and 14% in the placebo treated patients. These events are generally mild to moderate (NCI-
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, patients 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 (e.g. 2 
pieces of toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), 
generally a single agent antiemetic should be considered e.g. dopamine receptor antagonist, 
antihistamines or dexamethasone. 
5.4.2.3. Management of Renal Impairment    
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl 
falls below the threshold for study inclusion (≥ 51 ml/min), retesting should be performed 
promptly.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 67 of 128 
 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation 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 b.i.d. 
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 patients with severe renal impairment (creatinine clearance 
≤ 30 ml/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease is it recommended that olaparib be discontinued. 
5.4.3. Interruptions for Intercurrent Non-toxicity Related Events 
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 4 weeks for 
resolution of intercurrent conditions not related to disease progression or toxicity, the case 
should be discussed with GEICAM. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
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 needle biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient 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, patients 
should be advised to use caution while driving or using machinery if these symptoms occur.  
Table 9. Dose reductions for study treatment 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg twice daily 
250 mg twice daily 
200 mg twice daily 
 
5.4.4. Medication Errors and Overdose 
Medication errors may result in the administration or consumption of the wrong drug, by 
the wrong patient, at the wrong time or at the wrong dosage strength. If patient taking the 
lower dosing consciously/deliberately and not by mistake (e.g. if the patient is not 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 68 of 128 
 
tolerating the full dose very well), then this isn’t a medication error. Such medication errors 
occurring to a study participant are to be captured on the adverse event (AE) page of the 
eCRFs and on the SAE form when appropriate. In the event of medication dosing error 
GEICAM should be notified immediately. If an overdose or lower dose on olaparib occurs 
in the course of the study and it is associated with an AE (serious or not) are to be reported 
within 24 hours on a SAE form. Overdoses which are not associated with any AE can be 
reported within 30 days in a SAE form.  
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• 
Medication errors involving patient exposure to the product; 
• 
Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating patient.  
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error and, if applicable, any associated adverse event(s) is 
captured on an eCRF page (refer to Management, Timing and Assessment of Adverse 
Events section for further details). 
Please refer to section 11.1 for specific management of overdoses.  
5.5. General Concomitant Medication and Supportive Care Guidelines 
Patients must be instructed not to take any additional medication (over-the-counter or other 
products) during the study without prior consultation with the Investigator. The use of any 
natural/herbal products or other “folk remedies” should be discouraged but use of these 
products, as well as use of all vitamins, nutritional supplements and all other concomitant 
medications from 28 days prior to the start of study treatment and up to approximately 30 
days following the last dose of investigational product and the reason for their 
administration must be recorded in the eCRF. 
Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral), does not need to be recorded. Anaesthetics used for 
any surgical procedures performed during the patient’s participation in the study can be 
recorded as “unspecified anaesthesia” on the concomitant treatment records; it is not 
necessary to list the specific anaesthetics. Palliative and supportive care for cancer-related 
symptoms will be offered to all patients in this study. 
5.5.1. Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
Replacement Therapy (HRT) is acceptable), radiotherapy, biological therapy or other novel 
agent) is to be permitted while the patient is receiving study medication. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 69 of 128 
 
Live virus and live bacterial vaccines should not be administered whilst the patient 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. 
5.5.2. Restricted concomitant medications 
5.5.2.1. Strong or Moderate CYP3A inhibitors  
Known strong CYP3A inhibitors or moderate CYP3A inhibitors should not be taken with 
olaparib. While there is not an exhaustive list of CYP3A inhibitors the table below covers 
known CYP3A inhibitors. 
Table 10. CYP3A inhibitors 
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; the reductions should be made as follows:  
• 
Strong CYP3A inhibitors – reduce the dose of olaparib to 100 mg b.i.d. 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 b.i.d 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. 
 
CYP 
Enzymes  
Strong Inhibitors   
≥ 5-fold increase in AUC  
or > 80% decrease in 
Clearance (CL) 
Moderate inhibitors  
≥ 2 but < 5-fold increase in 
AUC 
or 50-80% decrease in CL 
Weak inhibitors 
≥ 1.25 but < 2-fold 
increase in AUC 
or 20-50% decrease in 
CL 
CYP3A 
Boceprevir, clarithromycin, 
conivaptan, grapefruit juice, 
indinavir, itraconazole, 
ketoconazole, 
lopinavir/ritonavir, 
mibefradil, nefazodone, 
nelfinavir, posaconazole, 
ritonavir, saquinavir, 
telaprevir, telithromycin, 
voriconazole,  boosted 
protease inhibitors 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit 
juice 
imatinib, verapamil 
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, cyclosporine, 
fluoxetine, fluvoxamine, 
ginkgo, goldenseal, 
isoniazid, nilotinib, oral 
contraceptives, ranitidine, 
ranolazine, 
tipranavir/ritonavir, 
zileuton 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 70 of 128 
 
In case of doubt about the procedure for concomitant administration of CYP3A inhibitors, 
the investigator should contact with GEICAM study team in order to avoid protocol 
deviations. 
5.5.2.2. Strong or Moderate CYP3A inducers 
Strong and moderate CYP3A inducers of CYP3A should not be taken with olaparib. While 
there is not an exhaustive list, table 11 covers known CYP3A inducers. 
Table 11. CYP3A inducers 
CYP Enzymes 
Strong Inducers 
≥ 80% decrease in AUC 
Moderate Inducers 
50-80% decrease in AUC 
Weak Inducers 
20-50% decrease in AUC 
CYP3A 
Avasimibe, carbamazepine, 
phenytoin, rifampicin, St. 
John’s wort, rifapentine, 
rifabutin, phenobarbital, 
nevirapine, enzalutamide. 
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin 
Amprenavir, aprepitant, 
armodafinil, echinacea, 
pioglitazone, prednisone, 
rufinamide 
 
If the use of any strong or moderate CYP3A inducers are considered necessary for the 
patient’s safety and welfare this could diminish the clinical efficacy of olaparib. 
If a patient requires use of a strong or moderate CYP3A inducer or inhibitor then they must 
be monitored carefully for any change in efficacy of olaparib. 
5.5.3. P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (e. g.  amiodarone, azithromycin) 
may increase exposure to olaparib. Caution should therefore be observed. 
5.5.4. Other Concomitant Medications 
Based on limited in vitro data, olaparib may increase the exposure to substrates of 
CYP3A4, P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  
Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP3A4, 
CYP1A2, 2B6, 2C9, 2C19 and P-gp.  
The efficacy of hormonal contraceptives may be reduced if co-administered with olaparib.  
Caution should therefore be observed if substrates of these isoenzymes or transporter 
proteins are co-administered.  
Examples of substrates include: 
• 
CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• 
CYP1A2 – duloxetine, melatonin 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 71 of 128 
 
• 
CYP2B6 – bupropion, efavirenz 
• 
CYP2C9 – warfarin  
• 
CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• 
P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• 
OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• 
OCT1, MATE1, MATE2K – metformin 
• 
OCT2  - serum creatinine 
• 
OAT3  -furosemide, methotrexate 
Any medications, with the exceptions noted in Section 5.5., which are considered necessary 
for the patient's welfare, and which it is believed will not interfere with the study 
medication, may be given at the discretion of the Investigator, providing the medications, 
the doses, dates and reasons for administration are recorded in the eCRF. 
Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications, and palliation. Any medication intended solely for supportive care (e.g., 
analgesics, anti-diarrhoeals, antidepressants) may also be used at the Investigator’s 
discretion. All medications should be recorded in the eCRF.  
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during 
the study period must be recorded in the eCRF. 
The reason(s) for the use, doses and dates of treatment should be recorded in the patient’s 
medical records and appropriate section of the eCRF. 
Anticoagulant Therapy 
Patients who are taking warfarin may participate in this trial; however, it is recommended 
that international normalised 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.  
Anti-emetics/Anti-diarrhoeals 
If a patient develops nausea, vomiting and / or diarrhoea, then these symptoms should be 
reported as AEs (see section 8.2.7. Safety Analyses) and appropriate treatment of the event 
given. 
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 the patient undergoes therapeutic palliative 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
Administration of other Anti-cancer Agents 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 72 of 128 
 
Patients must not receive any other concurrent anti-cancer therapy, including 
investigational agents, while on study treatment. Patients 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.  
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer and/or details of surgery for the 
treatment of the cancer, after discontinuation of treatment, will be collected. Reasons for 
starting subsequent anti-cancer therapies including access to other PARP inhibitors or 
investigational drugs will be collected and could be included in the exploratory assessments 
of OS. 
5.6. Treatment Compliance 
Patients will be required to return all bottles of olaparib as well as the completed patient 
diary at the beginning of each cycle for drug accountability. Drug accountability will be 
performed on day 1 of every 28-day cycle (+/- 7 days) prior to dispensing drug supply for 
the next cycle. The number of remaining tablets of olaparib will be documented and 
recorded. Compliance will be assessed by the tablet count and the information should be 
recorded in the appropriate section of the eCRF. 
The patient number should be recorded on the bottle label at time of assignment to a 
patient. Site personnel must ensure that patients clearly understand the instructions on how 
and when to take their study treatment. Patients will self-administer study treatment. 
Patients should be given a sufficient supply to last until their next study visit. Unused drug 
and/or empty bottles should be returned to the site at the next visit. The remaining tablets 
will not be returned to the patient, but will be retained by the investigative site, the site 
must obtain authorization from the Sponsor before destroy it. 
Dose adjustments must follow instructions provided in the dose adjustment guidelines 
section. 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 73 of 128 
 
6. Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of Assessments 
Study procedures and their timing (including tolerance limits for timing) are summarized in 
the Study Schedule, Protocol Attachment 1. 
6.1. Efficacy Assessments 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
According to RECIST v.1.1 in case of patients with a global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease progression at 
that time every effort should be made to document objective progression, even after 
discontinuation of treatment. The objective response status of such patients should be 
determined considering RECIST v.1.1 instructions, regarding situations where not all basal 
lesions can be evaluated. In case any efficacy assessment can be done they will be 
considered not evaluable for those efficacy endpoints applicable. 
6.1.1. Primary Efficacy Assessments 
The primary efficacy variable is Objective Response Rate (ORR).  
Tumour response will be assessed using RECIST v.1.1. Tumour assessment will be 
performed at baseline; the same method of measurement used at baseline will be used for 
further assessments, which will be conducted every 8 weeks (+/- 1 week). Responses 
should be confirmed according to RECIST v.1.1 after at least 28 days.  
The best response across treatment will be recorded. ORR is defined as the percentage of 
patients with a complete or partial response out of the total of patients in the considered 
study population (refer to section 8.2.1. Patient Populations).  
6.1.2. Secondary Efficacy Assessments 
Secondary efficacy assessments are PFS, CBR, RD, and OS:  
✓ Progression Free Survival (PFS): is defined as the time from study enrolment to the 
first documented progressive disease, using RECIST version 1.1., or death from any 
cause, whichever occurs first. 
✓ Clinical Benefit Rate (CBR): is defined as complete response (CR), partial response 
(PR), or stable disease (SD) ≥ 24 weeks according to the RECIST version 1.1. 
✓ Response Duration (RD): is defined as the time from the first documentation of 
objective tumour response (CR or PR) to the first documented progressive disease 
using RECIST version 1.1, or to death due to any cause, whichever occurs first.   
✓ Overall Survival (OS): is defined as the time from the date of study enrolment to the 
date of death from any cause. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 74 of 128 
 
6.2. Safety Assessments  
Investigators are responsible for monitoring the safety of patients who have entered this 
study and for alerting GEICAM of any event that seems unusual. 
The Investigator is responsible for appropriate medical care of patients during the study. 
The Investigator remains responsible for following, through an appropriate health-care 
option, adverse events that are serious or that caused the patient to discontinue before 
completing the study. The patient should be followed until the event is resolved or 
explained. Frequency of follow-up evaluation is left to the discretion of the Investigator. 
During the course of the study, all patients entering the trial must be evaluated according to 
the schedule outlined in the flow charts and described below. The results of the evaluation 
will be recorded in the eCRF pages until the patients are not followed anymore. 
6.2.1. Timing of Assessments 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
Physical examination will include vital signs assessments (blood pressure, pulse and 
body temperature) and performance status evaluation. Clinical signs and symptoms of 
disease recurrence should be further investigated as appropriate. 
Resting 12-lead ECGs are required within 7 days prior to starting study treatment and 
when clinically indicated. 
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for 
at least 5 minutes in each case. The Investigator or designated physician will review the 
paper copies of each of the timed 12-lead ECGs on each of the study days when they are 
collected. 
ECGs will be recorded at 25 mm/sec. All ECGs should be assessed by the Investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal. If 
there is a clinically significant abnormal finding, the Investigator will record it as an AE on 
the eCRF.  The original ECG traces must be stored in the patient medical record as source 
data. 
The following safety laboratory assessments will be performed by the local laboratories, 
at the times specified in the Study Schedule: 
• 
Haematology: Full haematology assessments for safety (haemoglobin, red blood 
cells [RBC], platelets, mean cell volume [MCV], mean cell haemoglobin 
concentration [MCHC], mean cell haemoglobin [MCH], white blood cells [WBC], 
absolute differential white cell count [neutrophils, lymphocytes, monocytes, 
eosinophils and basophils] and absolute neutrophil count or segmented neutrophil 
count and band forms) should be performed at each visit and when clinically 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 75 of 128 
 
indicated. If absolute differentials are not available % differentials should be 
provided. Study visits for safety assessments will be scheduled on baseline visit and 
day 8 (+/- 3 days) of cycle 1 and in subsequent cycles every 28 days (+/- 7 days). 
This analysis should be performed also in the 30-day post-discontinuation follow-up 
evaluation performed 30 days (+/- 7 days) following the discontinuation of study 
treatment. In case the beginning of this new therapy cannot be delayed as per the 
investigator’s judgment, the safety visit may be performed in advance, but always 
before starting with the new anticancer therapy. 
If treatment is discontinued close to the theoretical date for the next cycle and it is 
not planned to perform in advance the post-treatment visit due to the initiation of a 
new anticancer therapy, a new haematology analysis should be performed at the 
moment of the study treatment discontinuation.  
• 
Coagulation testing: Activated partial thromboplastin time (aPTT) and 
international normalised ratio (INR) will be performed at baseline and if clinically 
indicated unless the patient is receiving warfarin. Patients taking warfarin may 
participate in this study; however, it is recommended that prothrombin time (INR 
and aPTT) be monitored carefully at least once per week for the first month, then 
monthly if the INR is stable. 
• 
Blood Chemistry: sodium, potassium, calcium, magnesium, fasting glucose, 
creatinine, total bilirubin, gamma glutamyltransferase (GGT), alkaline phosphatase 
(AP), aspartate transaminase (AST), alanine transaminase (ALT), urea or blood urea 
nitrogen (BUN), total protein, albumin and lactic dehydrogenase (LDH) should be 
performed. 
In case a subject shows an AST or ALT ≥ 3 x ULN or total bilirubin ≥ 2 x ULN 
please refer to Appendix 5 “Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law”, for further instructions.  
• 
Similar to haematology test, blood chemistry analysis should be performed on 
baseline visit, day 8 (+/- 3 days) of cycle 1 and in subsequent cycles every 28 days 
(+/- 7 days) and if clinically indicated. This analysis should be performed also in the 
30-day post-discontinuation follow-up evaluation performed 30 days (+/- 7 days) 
following the discontinuation of study treatment. In case the beginning of this new 
therapy cannot be delayed as per the investigator’s judgment, the safety visit may be 
performed in advance, but always before starting with the new anticancer therapy. 
If treatment is discontinued close to the theoretical date for the next cycle and it is 
not planned to perform in advance the post-treatment visit due to the initiation of a 
new anticancer therapy, a new haematology analysis should be performed at the 
moment of the study treatment discontinuation.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 76 of 128 
 
• 
Urinary testing: Urinalysis by dipstick should be performed at baseline and then 
only if clinically indicated. Microscopic analysis should be performed by the 
hospital’s local laboratory if required. 
• 
Serum or urine pregnancy test: Two pregnancy tests on blood or urine samples 
must be performed for pre-menopausal women of childbearing potential, one within 
28 days prior to the start of study treatment and the other on Day 1 of the study 
prior to commencing treatment.  Tests will be performed by the hospital’s local 
laboratory. If results are positive the patient is ineligible/must be discontinued from 
the study.  In the event of a suspected pregnancy during the study, the test should be 
repeated. 
• 
Bone marrow or blood cytogenetic analysis may be performed according to 
standard haematological practice for patients with prolonged haematological 
toxicities as defined in Section 5.4.1.3. Management of Prolonged Haematological 
Toxicities while on Study Treatment. 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. If findings are consistent with 
MDS/AML, study drug should be discontinued and a full description of findings 
should be submitted with an SAE report by the Investigator to GEICAM for 
documentation on the Patient Safety database. Presence or absence of blood 
cytogenetic abnormalities and flow cytometry will be documented on the clinical 
database.      
• 
Additional analyses may be performed if clinically indicated. All AEs (and their 
relatedness to the study drugs/medications) occurring during the study will be 
repeated as clinically indicated and documented in the eCRF. AEs will be graded 
according to NCI-CTCAE version 4.0. 
6.2.2. Definitions 
The safety definitions are described in the table 12. 
Table 12. Safety definitions 
Concept 
Definition 
Adverse Event  (AE) 
An adverse event is the development of an undesirable 
medical condition or the deterioration of a pre-existing 
medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally 
related to the product.  An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 77 of 128 
 
investigation (e.g., laboratory findings, electrocardiogram).  
In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious 
AEs. 
Laboratory abnormalities should be reported as AE only in 
case they lead to an action on study treatment or if they are 
serious. 
Adverse Reaction (AR) 
All untoward and unintended responses to a medicinal 
product related to any dose administered.  
All expected ARs are listed in the Investigator's Brochure 
(IB) in case of not authorized investigational product or 
Summary of Product Characteristics [SmPC] in case of an 
authorized investigational product. If the nature or the 
severity of an adverse reaction is not consistent with the 
applicable product information, the AR is defined as 
unexpected. The basis for the decision is the current version 
of the corresponding reference document that has been 
submitted and approved by the competent authority and the 
ethics committees. 
Accountability criteria 
The sponsor will classify the adverse event, based in their 
causation relation with the investigational product, following 
the Karch and Lasagna algorithm (1977)72, as: 
• Final: there is reasonable temporal sequence between the 
drug administration and the existence of the adverse 
event. This event matches with the adverse reaction 
described for the investigational product, improves with 
the omission and reappears after its re-administration and 
can’t be explained by other causes. 
• Probable: there is reasonable temporal sequence between 
the investigational product administration and the 
appearance of the adverse event. This event matches with 
the adverse reaction described for the drug, improves with 
the omission and can’t be explained by other causes. 
• Possible: there is reasonable temporal sequence between 
the investigational product administration and the 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 78 of 128 
 
appearance of the adverse event. This event matches with 
the adverse reaction described for the drug but can be 
explained by other causes. 
• Conditional or improbable: there is reasonable temporal 
sequence 
between 
the 
investigational 
product 
administration and the appearance of the adverse event. 
This event does not matches with the adverse reaction 
described for the drug and can be explained by other 
causes. 
• Not related: there is no reasonable temporal sequence 
between the investigational product administration and 
the appearance of the adverse event. This event does not 
matches with the adverse reaction described for the drug 
and can be explained by other causes. 
For expedited reporting purposes it is considered as related 
the categories: final, probable and possible from Karch and 
Lasagna algorithm (1977) and as not related the category 
conditional or improbable of that algorithm.  
The determination of the possible relation with the study 
treatment is responsibility of the Principal Investigator of the 
site or the person designated by him.  
Serious Adverse Event 
(SAE) and Serious Adverse 
Reaction (SAR) 
A serious adverse event is an AE occurring during any study 
phase (e.g., screening, treatment, wash-out, follow-up), at 
any dose of the study drugs that fulfils one or more of the 
following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of 
existing hospitalization  
• Results in persistent or significant disability or incapacity  
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the 
patient or may require medical intervention to prevent 
one of the outcomes listed above. 
The causality of SAEs (their relationship to all study 
treatment/procedures) will be assessed by the Investigator(s) 
and communicated to Pharmacovigilance Department of 
GEICAM. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 79 of 128 
 
The following events will be considered as AEs of Special 
Interest (AESIs) and they have to be documented as a SAE 
and notified to the Pharmacovigilance Department of 
GEICAM immediately: Development of MDS/AML, new 
primary 
malignancy 
(other 
than 
MDS/AML) 
and 
pneumonitis. Overdose and medication errors should be 
reported as indicated in section 5.4.4. and 11.1.  
Any temporary increase in the severity of a symptom or 
previous sickness that happens after the baseline of the study 
is considered also as an adverse event.  
Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) 
Any serious adverse reaction whose nature, intensity or 
consequences do not correspond with the reference 
information for the investigational product (example, 
Investigator Brochure [IB] in case of not authorized 
investigational 
product 
or 
Summary 
of 
Product 
Characteristics 
[SmPC] 
in 
case 
of 
an 
authorized 
investigational product).  
The unexpected nature of an adverse reaction is based in the 
fact of not being observed previously and not in what could 
be advanced based on the pharmacological properties of the 
drug.  
 
6.2.3. Management, Timing and Assessment of Adverse Events 
AE Classification  
 
Adverse events should be classified following version 4.0 of 
the NCI-CTCAE.  A copy can be downloaded in the NCI web 
site: http://evs.nci.nih.gov/ftp1/CTCAE. The Investigators team 
must have access to the NCI-CTCAE version 4.0.  
The AE not included in the CTCAE will be classified as 
described on Protocol Attachment 3. 
The causal relationship between the investigational product and 
the AE will be assessed by the Investigator using the Karch and 
Lasagna (1977) algorithm. 
Procedure to notify an 
AE to GEICAM 
The site must notify to GEICAM, through eCRF, the following 
events: 
• All adverse events that occur after signed any of the study 
Informed Consent Forms.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 80 of 128 
 
• Pre-existing conditions that get worse during the study.  
• The evaluation of the possible relationship of each adverse 
event to the study drugs/medications or protocol procedure.  
• The circumstances and data that causes the suspension of 
the treatment of a patient due to an adverse event. 
• The events leading to the clinical outcome of death from 
disease progression will be included in the efficacy analysis 
and are not recorded as adverse events, unless the 
Investigator believes they could have been caused by the 
study drugs/medications or if the cause is not clearly due to 
disease progression.  
Recording of adverse 
events 
 
The following variables will be collected for each AE: 
• AE (verbatim). 
• The date when the AE started and stopped.  
• Whether the AE is serious or not. 
• Investigator causality rating against the IMP (yes or no). 
• Action taken with regard to IMP. 
• Outcome. 
• Changes in NCI-CTCAE grade and the maximum CTC 
grade attained. 
In addition, the following variables will be collected for SAEs: 
• Date AE met criteria for serious AE. 
• Date Investigator became aware of serious AE. 
• AE is serious due to. 
• Date of hospitalization. 
• Date of discharge. 
• Probable cause of death. 
• Date of death. 
• Autopsy performed. 
• Description of AE. 
• Causality assessment in relation to Study procedure(s). 
• Causality assessment in relation to other medication. 
It is important to distinguish between serious and severe AEs.  
Severity is a measure of intensity (minor/mild/severe) whereas 
seriousness is defined by the criteria in 6.2.2. Definitions. An AE 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 81 of 128 
 
of severe intensity need not necessarily be considered serious. 
For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE. On the other hand, a 
stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be a SAE. 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred 
(when possible) to recording a list of signs and symptoms.  
However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately. 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated 
laboratory values and vital signs should therefore only be 
reported as AEs if they fulfil any of the SAE criteria or are the 
reason for dose modification or discontinuation of treatment 
with olaparib. If deterioration in a laboratory value/vital sign is 
associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional 
information. Wherever possible the reporting Investigator uses 
the clinical, rather than the laboratory term (e.g., anaemia 
versus low haemoglobin value). In the absence of clinical signs 
or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due 
to disease progression, should not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical 
finding at a physical examination as compared with the baseline 
assessment will be reported as an AE. 
N.B. Cases where a subject shows an AST or ALT ≥ 3 x ULN 
or total bilirubin ≥ 2 x ULN may need to be reported as SAEs, 
please, refer to Appendix 5 ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – 
Hy’s Law’, for further instructions. 
Disease progression 
Disease progression can be considered as a worsening of a 
subject’s condition attributable to the disease for which the 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 82 of 128 
 
investigational product is being studied.  It may be an increase in 
the severity of the disease under study and/or increases in the 
symptoms of the disease. The development of new, or 
progression of existing metastasis to the primary cancer under 
study should be considered as disease progression and not an 
AE. Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study. 
New cancers 
The development of a new primary cancer (including skin 
cancer) should be regarded as an AE of special interest and will 
generally meet at least one of the serious criteria (see Section 
6.2.4 for reporting instructions).  New primary malignancies are 
those that are not the primary reason for the administration of the 
study treatment and have developed after the inclusion of the 
patient into the study.  They do not include metastases of the 
original cancer.  Symptoms of metastasis or the metastasis itself 
should not be reported as an AE/SAE, as they are considered to 
be disease progression.  
Lack of efficacy 
When there is deterioration in breast cancer, there may be 
uncertainty as to whether this is lack of efficacy or an AE.  In 
such cases, unless the Sponsor or the reporting physician 
considers that the study treatment contributed to the deterioration 
of the condition, or local regulations state to the contrary, the 
deterioration should be considered to be a lack of efficacy and 
not an AE. 
Deaths: please, refer to Section 6.2.4. 
Timing and assessment 
of AE (see Protocol 
Attachment 4) 
The site staff will report on the eCRF the information of the AE 
in the following  periods: 
• Baseline (after 
ICD 
and 
before 
study 
drug/medications): study site personnel will note the 
occurrence 
and 
nature 
of 
each 
patient´s 
medical 
condition(s) and pre-existing conditions in the appropriate 
section of the eCRF. If a patient never receives study 
drug/medications but experiences an adverse event after the 
ICD is signed, ONLY events the Investigator believes may 
have been caused by a protocol procedure will be reported 
to GEICAM via eCRF. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 83 of 128 
 
• During treatment with the study drug: during the study, 
site personnel will record any change in the condition(s) 
and the occurrence and nature of any adverse events. A 
CTCAE grade rating will be assigned before each cycle for 
any adverse event experienced during the previous cycle.  
• 30-day post- treatment follow-up period: each patient 
will have a 30-day post-discontinuation follow-up 
evaluation 
approximately 
30 
days 
following 
the 
discontinuation of study treatment. Patients should be 
closely followed for study treatment adverse events in order 
to detect delayed toxicity. If drug-related toxicity is present 
beyond 30 days post-discontinuation, patients must be 
followed until the toxicity resolves or improved to baseline, 
the relationship is reassessed as unrelated, the Investigator 
confirms that no further improvement can be expected, 
another therapy is initiated, or death.  
• Long-Term Follow-up Period (after the 30-day post-
discontinuation):  
For Pharmacovigilance purposes and characterization, any 
case of MDS/AML or new primary malignancy occurring 
after the 30 day follow up period should be reported to 
GEICAM whether it is considered a non-serious AE [e.g. 
non-melanoma skin cancer] or SAE, and regardless of 
investigator’s assessment of causality.  Investigators will be 
asked during the regular follow up for overall survival if 
the patient has developed MDS/AML or a new primary 
malignancy and prompted to report any such cases.   
At any time after a patient 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 
or 
protocol 
procedure, 
the 
investigator should notify GEICAM. 
If patients 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. 
Other new and ongoing SAEs thought to be related to study 
drug/medications or protocol procedures should be 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 84 of 128 
 
documented on the eCRF and immediately reported to 
GEICAM via the designated transmission method, even if 
the study has been closed. 
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 patients. This includes 
new AEs/SAEs in patients still being followed up for 
survival but who have completed the post treatment follow 
up period (30 days). 
 
6.2.4. Management, Timing and Assessment of SAEs 
Timing of SAEs (see 
Protocol Attachment 4) 
All the SAEs (either spontaneously or during the trial visits) will 
be collected since the patient signs the Informed Consent 
Document (ICD). 
All the SAEs must be documented in the medical record of the 
patient and in the eCRF. All study-related toxicities/ SAEs must 
be followed until resolution, unless in the Investigator’s opinion, 
the condition is unlikely to resolve due to the patient’s 
underlying disease. 
Pregnancies 
If a patient becomes pregnant while enrolled on a GEICAM 
study, it must be reported in the Pregnancy Form and sent to the 
GEICAM pharmacovigilance department within 24 hours of 
becoming aware of it. 
SAEs which do not need 
to be notified to the 
Pharmacovigilance 
Department of 
GEICAM  
The following events are not considered SAEs: 
• A visit to the emergency room or other hospital department 
lasting less than 24 hours that does not result in admission 
(unless considered an “important medical event” or a life-
threatening event). 
• Elective surgery planned before signing consent. 
• Hospitalization which is due solely to a planned study visit 
and without prolongation. 
• Routine health assessment requiring admission for 
baseline/trending 
of 
health 
status 
(e.g. 
routine 
colonoscopy). 
• Medical/surgical 
admission for purpose other than 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 85 of 128 
 
remedying ill health state that was planned before study 
entry. Appropriate documentation is required in these cases. 
• Admission encountered for another life circumstance that 
carries no bearing on health status and requires no 
medical/surgical intervention (e.g. lack of housing, 
economic 
inadequacy, 
caregiver 
respite, 
family 
circumstances, administrative). 
• Progression of the malignancy during study (including 
signs and symptoms of progression), unless the outcome is 
fatal and death occurred before end of treatment. Thereafter 
death due to disease progression has not to be reported as 
SAE.  
• Hospitalization due to signs and symptoms of disease 
progression. 
• An overnight stay in the hospital that is only due to 
transportation, organization or accommodation problems 
and without medical background.  
They will be reported in the eCRF and in the patient record. 
The rest of SAEs must be notified as described as follows. 
Procedure to notify a  
SAE to the  
Pharmacovigilance 
Department of 
GEICAM 
The SAEs must be notified to the Pharmacovigilance 
Department of GEICAM. A member of the Investigator team 
must complete and sign the GEICAM SAE notification form 
which will be sent by fax/mail, immediately and always during 
the 24 hours following knowledge of the SAE: 
Pharmacovigilance Department of GEICAM  
Fax: +34 917 371 619 
farmacovigilancia@geicam.org  
GEICAM will review the received form and, if necessary, will 
ask more information to the Investigator. 
When additional information is obtained about the SAEs, or this 
is solved or is improbable it will change, a follow-up report must 
be also completed and sent by fax/mail, immediately and always 
during the following the 24 hours to the Pharmacovigilance 
Department of GEICAM. 
If GEICAM suspects that the SAE could be a SUSAR, the 
Investigator should give the follow up information requested. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 86 of 128 
 
All SAEs/AESIs from the time the patient have the first dose of 
the study drug/medications through 30 days following the last 
administration of study drug/medications must be reported 
according to the procedure described below. All SAE regardless 
of timing must be reported, if considered related to study 
drug/medication. 
Likewise, progression of a patient's underlying condition leading 
to one of the above should also not be reported as a SAE, but 
documented as primary study endpoint. 
GEICAM will report all SAEs and AESIs immediately to the 
Chief Investigator.  
All SAEs and AESIs will be followed-up by the Investigator 
until satisfactory resolution. Annually all SARs will be reported 
as the DSUR to the competent authorities and the leading ethics 
committee, including all SUSARs.  
Withdrawal from further treatment shall be at the discretion of 
the Investigator. 
Adverse Events of 
Special Interest (AESIs) 
 
Adverse events of special interest [AESI] 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 GEICAM. An AESI may 
be serious or non-serious. Adverse Events of Special Interest for 
olaparib are the Important Potential Risks of MDS/AML, new 
primary malignancy (other than MDS/AML) and pneumonitis.  
ANY event of MDS/AML, new primary malignancy, or 
pneumonitis should be reported to GEICAM immediately 
(within 24 hours following knowledge of the event), as per the 
SAE notification instructions whether it is considered a non-
serious AE [e.g. non-melanoma skin cancer] or SAE, and 
regardless of investigator’s assessment of causality.    
A questionnaire will be sent to any investigator reporting these 
AESIs, as an aid to provide further detailed information on the 
event.  During the study there may be other events identified as 
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. 
For information about overdose and medication errors please 
refers to sections 5.4.4. and 11.1. Overdose.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 87 of 128 
 
AST or ALT ≥ 3 x ULN 
or total bilirubin ≥ 2 x 
ULN 
Cases where a subject shows an AST or ALT ≥ 3 x ULN or 
total bilirubin ≥ 2 x ULN could need to be reported as SAEs, 
please, refer to Attachment 5 ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – 
Hy’s Law’, for further instructions. 
Death on Study 
Deaths:  
All deaths that occur during the study, or within the 
protocol-defined 30-day post-study follow-up period after the 
administration of the last dose of study treatment, must be 
reported as follows: 
• Where death clearly is the result of disease progression 
should be reported to the study monitor at the next 
monitoring visit and should be documented in the eCRF but 
should not be reported as an SAE unless they occurred 
before end of treatment. 
• 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 the study monitor as a 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.  
This information can be captured in the ‘death eCRF’. 
• Deaths with an unknown cause should always be reported 
as a SAE. A post mortem maybe helpful in the assessment 
of the cause of death, and if performed a copy of the post-
mortem results should be forwarded to GEICAM (within 
the usual timeframes). 
• Deaths after the end of study which are considered to be 
related to study treatment have to be reported as SAEs. 
To the extent feasible sufficient information including relevant 
laboratory values, ECG, scan, biopsy or autopsy results must be 
provided by the Investigator in the SAE narrative (even if 
Investigator determines the SAE is not related) so as to permit 
an independent causality assessment by a Competent Authority. 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 88 of 128 
 
6.2.5. Management, Timing and Assessment of SUSARs 
Expedited Notification 
of  SUSAR to the 
Competent Authorities 
The Pharmacovigilance Department of GEICAM is responsible 
to notify to each of the competent authorities of the participating 
countries, all the SUSARs collected in the study, following the 
procedures shown in the current legislation.   
Timing of notification  
The deadline for reporting a SUSAR shall be 15 calendar days 
from when GEICAM becomes aware of it. When suspected 
SUSAR caused the death of the patient or endangered her life, 
GEICAM will send the information within 7 calendar days from 
the date on which it becomes aware. This information must be 
completed, if possible, in the next 8 days. 
This information must also be sent to AstraZeneca at the same 
time as it is sent to the Regulatory Authorities. 
Expedited reporting of 
other relevant safety 
information 
GEICAM will also notify, expeditiously, all the information that 
could modify the balance benefit/risk of the investigational 
product, or determine changes in its administration pattern or in 
the study performance, such as: 
• 
A qualitative change or an increase in the percentage of 
occurrence of the SAR expected, which are considered 
clinically significant. 
• 
The SUSAR occurring after completion of the study and 
are reported by the Investigator to the sponsor.  
• 
New events related to the conduct of a trial or the 
development of an IMP likely to affect the safety of 
patients, such as: 
✓ SAE that could be related with the study procedure 
and could modify the conduct of the trial. 
✓ A significant risk to patients such as lack of efficacy 
in a drug used to treat a life-threatening illness. 
✓ A major safety finding from a newly completed 
animal study (such as carcinogenicity). 
✓ A temporary halt of a trial for safety reasons if the 
trial is conducted with the same investigational 
medicinal products in another country and if this 
information is known by GEICAM. 
✓ Any recommendation of the IDMC that is relevant to 
the safety of patients (if applicable). 
This relevant information shall be notified as soon as possible 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 89 of 128 
 
and no later than 15 days after GEICAM becomes aware of it. 
Additional information will also be notified as quickly as 
possible.  
Development Safety 
Update Report (DSUR) 
The DSUR that includes the SAEs and SUSARs collected during 
the study will be sent by GEICAM to the Competent Authorities 
and EC/IRB at the time established by the current legislation. 
Notification to  
Investigators 
GEICAM will communicate to the Investigators any safety 
information that may affect the safety of trial patients, as soon as 
possible.  
Information on SUSAR occurred during the study will be sent 
quarterly, in aggregate, in a list along with a brief analysis of the 
data provided.  
They will be informed also, throughout the entire study, of any 
safety aspect that impacts the performance on the clinical trial or 
in the product development, including the interruption or 
modification in the development program of the protocol safety-
related.  
 
6.3. Biological sampling procedures 
6.3.1. Biological Samples  
Detailed instructions for the collection, handling and shipment of biological samples are 
outlined in the Sample Management Manual (SMM). The following table summarizes all 
samples required during study conduction. 
Table 13. Biological Samples 
Sample type 
 Visits 
Requirements 
Whole blood sample for 
gBRCA mutational 
testing. 
Blood sample could be sent either: 
1) During the line of treatment previous to 
study entry, if the patient is considered a 
potential candidate for the study (at least the 
patient must have measurable and biopsiable 
disease). 
or  
2) During screening, after ending the 
previous line of treatment, (simultaneously to 
the shipment of the tumour samples for 
Mandatory for 
eligibility of all 
registered patients, 
(unless BRCA 
mutational status is 
already known based 
on a Myriad previous 
report). 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 90 of 128 
 
methylation analysis).  
A specific ICF must be signed for this 
assessment. 
Metastatic tumour 
sample (FFPE) for 
prospective sBRCA 
methylation testing 
(strongly recommended 
to be obtained after 
previous therapy 
regimen) 
Remaining tissue to be 
used for secondary and 
exploratory objectives. 
- Screening  
 
Mandatory for 
eligibility  
Whole blood for BRCA 
retrospective 
methylation and 
expression analysis 
and/or perform other 
biomarker analysis 
 
- Screening 
In case it is not obtained at screening it should be 
obtained prior to start the study treatment 
(enrolled patients) or the next therapy (screening 
failure patients). 
 
Required for all 
registered patients  
  
- At the end of treatment (prior to next therapy 
regimen).  
If a patient ends treatment due to other cause 
different to disease progression, one additional 
sample should be collected once progression is 
documented, if feasible. 
Required for all 
enrolled patients 
Plasma samples for 
biomarker analysis 
- Screening:  
In case it is not obtained at screening it should be 
obtained prior to start study treatment (enrolled 
patients) or the next therapy (screening failure 
patients). 
Required for all 
registered patients 
- Between 4 to 6 weeks of treatment 
Required for all 
enrolled patients 
- At the end of treatment (prior to next therapy 
regimen). 
If a patient ends treatment due to other cause 
different to disease progression, one additional 
sample should be collected once progression is 
documented, if feasible. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 91 of 128 
 
Archival primary 
tumour sample (if 
available) 
- To be collected during the study 
Required for all 
registered patients, if 
available 
Biopsy from metastatic 
tumour 
sample 
at 
disease progression (if 
available) 
- At disease progression 
If the patient ends the study due to disease 
progression, it must be collected prior to next 
therapy regimen. If the patient ends treatment 
due to other cause different to disease 
progression, 
collect 
this 
sample 
once 
progression is documented. 
Required for all 
enrolled patients, if 
available 
The samples and data from this research will be coded and not identified with any personal 
details. Each sample will be identified with the study and patient number. In this way 
biomarker data may be correlated with clinical data, samples destroyed or returned in the 
event of withdrawal of consent and regulatory audit enabled. Access to the link between the 
biomarker sample and the individual patient are restricted to the Investigator and his 
collaborators, IEC, health authorities, monitors and auditors of the sponsor or its authorized 
agents, who are bound to secrecy inherent to their profession, when they are required to 
check the data and study procedures to ensure that the study is being done correctly and the 
data is accurate, but always maintaining the confidentiality of the same in accordance with 
current legislation. 
6.3.2. BRCA1 and BRCA2 Promoter Methylation Testing in Somatic DNA 
At least one paraffin sample from metastatic lesions is mandatory to perform methylation 
test and determine patient eligibility. Every effort should be done to obtain the sample after 
last treatment for metastatic disease, prior to the study entry. Surgery blocks or core 
biopsies would be acceptable, minimal amount of tumour tissue will be specified in the 
SMM.   
Tumour samples for methylation screening analysis must be sent  to the epigenetic central 
laboratory following shipment instructions in the SMM. Results from both analyses will be 
provided to Investigator within 8 working days after the day the samples are received in the 
central laboratory, unless extra-time is needed for justified reasons.  
The sBRCA methylation status result from the central laboratory assessment will be 
provided to the Investigator in order to determine subject eligibility. Investigator must 
explain to the patient that this assessment has unknown clinical significance in this moment 
and that the results of this trial will test the olaparib efficacy in patients with methylated 
sBRCA promoter, helping to elucidate if a relation between the methylation status and the 
response to olaparib may exist. If so, subsequent studies should be needed to confirm it.  
DNA from paraffin-embedded tumour samples will be obtained in a central pathology 
laboratory and sent to the central epigenetics laboratory for methylation assessment. There, 
DNA will be treated with sodium bisulphite which will induce the deamination of cytosine 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 92 of 128 
 
to uracil while 5-metilcytosine will remain as cytosine. BRCA1 and 2 CpG island 
methylation status will be established using pyrosequencing, a semi-quantitative method 
that will give a methylation value of each of the CpG dinucleotides included in the 
sequence to be analyse. Samples will be processed per triplicate, computing for each 
promoter CpG island (BRCA1 & BRCA2), average methylation values of CpG sites, 
considering as unmethylated whenever the value is lower than 25% (β≤0.25), while 
methylated status will be consider when methylation value is higher than 25% (β>0.25). If 
a modification of the cut-off value is deemed necessary it will be established in laboratory 
manual.  
Analysis will be performed using validated methods with defined acceptance criteria 
including the circumstances that require repeating analysis; positive and negative controls 
will be included in each analysis. 
6.3.3. Germline BRCA1 and BRCA2 Mutational Testing 
All patients must lack of deleterious or suspected deleterious germline BRCA mutation to 
be eligible; this will be assessed via central testing by Myriad unless test have been done 
previously at Myriad. 
Central BRCA assessment will require the shipment of one blood sample (9-10 ml) 
collected in EDTA tubes.  
Blood samples for mutational BRCA screening analysis must be sent to the central 
laboratory following shipment instructions in the SMM, once signed the specific ICF for 
this mutational analysis. Signature of ICF and shipment of blood samples could be 
performed either simultaneously to the shipment of the tumour samples for methylation 
analysis or before, in previous lines of treatment, once inclusion/exclusion criteria have 
been reviewed and the patient is considered a potential candidate to the study (at least the 
patient must have measurable disease and biopsiable disease).  
Results of BRCA mutation analysis will be provided to investigator within 10 working days 
after the day the samples are received in the central laboratory, unless extra-time is needed 
for justified reasons (e.g. in case of finding a variant of uncertain significance).  
The analysis will be performed in Myriad Genetics laboratories Inc.  at Salt Lake City 
(Utah, USA), using the BRACAnalysis CE test, which counts with the EU certificate about 
compliance of the directive 98/79/EC on in vitro diagnostic medical devices.   
The gBRCA mutational status result from the Myriad assessment will be provided to the 
Investigator and will be collected as part of the patient’s demography and medical history 
details. 
6.3.4. Other Biomarker Assessments 
The following samples will be collected to achieve secondary objectives and exploratory 
work. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 93 of 128 
 
Blood specimens: Blood samples will be collected prior and after treatment to assess 
germinal methylation status and mRNA levels of BRCA 1 and 2. Methylation data will be 
used to assess correlation of germinal methylation status with outcome data and evaluate 
correlation between germinal and somatic methylation status. BRCA expression results will 
be correlated with the methylation status and outcome data.  Changes of BRCA methylation 
and expression levels during the study and after progression will be explored.  
Blood samples will be also retained for exploratory biomarker analyses related to drug 
response or adverse drug reactions. Genomic, epigenetic, metabolomic and proteomic 
variation may help to explain some of the variability in response seen among different 
individuals. Comparing the DNA, RNA, protein, and metabolite patterns of patients who 
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment. For example, putative 
safety biomarkers, drug metabolizing enzyme genes, drug transport protein genes, or genes 
thought to be related to the mechanism of drug action may be examined. As indicated in 
table 13 blood samples prior to treatment will be collected for all registered patients, after 
treatment only from enrolled patients.  
Plasma Samples: blood samples collected at time-points showed in table 12 from all 
enrolled patients will be processed to obtain plasma in study sites. Plasma samples will be 
collected for exploratory analyses of circulating free DNA or RNA or other biomarkers and 
their relationship to resistance or sensitivity to treatment with olaparib. Plasma samples 
may also be analyzed to explore the pharmacodynamic (PD) treatment effects on the 
expression of specific biomarkers.  
Tumour Tissue: FFPE samples from primary and metastatic tumour will be collected as 
indicated in Table 13 in order to address correlation between primary and metastatic 
lesions. 
Retrospective, exploratory tumour tissue biomarkers, including DNA, RNA and protein 
analytes, could be analysed to investigate possible associations with resistance/sensitivity to 
treatment with olaparib. Examples of such biomarkers may include but not limited to 
somatic BRCA1/2 mutational status or other genes related to cancer susceptibility and 
though to be related to the drug mechanism of action. These samples will be instrumental to 
explore biomarkers of response and biomarkers of primary resistance to olaparib. 
The relationship between centrally assessed biomarkers and resistance/sensitivity to 
treatment with olaparib will be reported in an exploratory fashion.  
Blood and tumour samples for secondary and exploratory objectives will be sent to the 
central pathology laboratory where they will be kept until analysis is performed in analysis 
laboratories appointed by GEICAM. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 94 of 128 
 
7. Data Quality Assurance 
To ensure accurate, complete and reliable data, GEICAM will do the following: 
• Provide instructional material to the study sites, as appropriate 
• Sponsor a start-up training session to instruct the Investigators and study 
coordinators. This session will give instructions on the protocol, the completion of the 
eCRFs, and study procedures 
• Make periodic visits to the study site to review study progress, Investigator and 
patient compliance with the clinical trial protocol requirements and any emergent 
problems. 
• Be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
• Review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection 
• Conduct a quality review of the database  
• Verify the quality of the data 
To ensure the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the Investigator will keep records of laboratory tests, clinical notes, and 
patient medical records in the patient files as original source documents for the study. If 
requested, the Investigator will provide GEICAM, applicable regulatory agencies, and 
applicable ethical review boards with direct access to original source documents. 
7.1. Data Management and Registries File 
Data for this study will be recorded via an electronic data capture system using eCRFs. Data 
will be transcribed by the site from the paper source documents onto the eCRF. In no case the 
eCRF is to be considered as source data for this trial. The eCRFs must be completed in an 
electronic Data Base. That electronic Data Base carries out with the regulatory authorities 
requirements. It is the responsibility of the Investigator to maintain adequate and accurate 
eCRFs (according to the technology used) designed by GEICAM to record (according to 
GEICAM instructions) all observations and other data pertinent to the clinical investigation. 
All eCRFs should be completed in their entirety in a neat, to ensure accurate interpretation 
of data. 
Should a correction be made, the corrected information will be entered in the eCRF 
overwriting the initial information. An audit trail allows identifying the modification.  
Data are available within the system to GEICAM as soon as they are entered in the eCRF. 
The computerized handling of the data by GEICAM when available in the eCRF may 
generate additional requests to which the Investigator is obliged to respond by confirming 
or modifying the data questioned. The requests with their responses will be managed 
through the eCRF. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 95 of 128 
 
8. Sample Size and Statistical Methods 
8.1. Determination of Sample Size 
8.1.1. Sample Size Determination  
We have set the null hypothesis (H0) that ORR will be 30% (ORR achieved by TN patients 
treated with gemcitabine plus carboplatin1) versus the alternative hypothesis (H1) that ORR 
will be 54% (ORR showed by TN BRCA mutated patients treated with olaparib2). Using an 
optimal two-stage Simon model and considering an alpha error of 0.05 and a statistical 
power of 80%, it will be required to include 31 evaluable patients. Twelve evaluable 
patients will be enrolled in the first stage, and if at least 4 patients of them have response, 
additional patients will be recruited to get a total of 31 evaluable patients. Assuming a 10% 
dropout rate, the total number of patients to be enrolled is 34. Considering, these data the 
number of responders needed at the end of stage 2 to reject the null hypothesis is at least 14 
responders. 
8.2. Statistical and Analytical Plans 
8.2.1. General Considerations 
Statistical analysis of this study will be the responsibility of GEICAM. The interpretation 
of study results will be the responsibility of the Chief Investigator of the study.   
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be dated and 
maintained by GEICAM. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition and/or its analysis 
will also be reflected in a protocol amendment. 
All analysis will be performed using the SAS Enterprise Guide 5.1 version. 
8.2.1. Patient Populations 
Intent to treat population (ITT): The ITT population will include all patients who are 
enrolled in the study.   
Efficacy population: a subset of the ITT population that have received at least one dose of 
study medication and has performed at least one tumour response assessment according to 
RECIST v.1.1 (unless a progression, death or unacceptable toxicity is seen before the first 
tumour response assessment) and without major protocol deviations according to the 
protocol deviation manual.  
The efficacy population will be the primary population for the efficacy analysis.  
It will be performed a sensitivity analysis using the ITT population. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 96 of 128 
 
Safety population: will include all patients enrolled in the study who received at least one 
dose of treatment. This population is for the safety analysis.  
Population for Biomarker Analysis: a subset of enrolled patients with evaluable blood 
and/or tumour samples required for achievement of the secondary and exploratory 
objectives of the study. 
8.2.2. Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
• 
Summary of patients entered and by site. 
• 
Total number of patients entered. 
• 
Total number of patients enrolled. 
• 
Summary of reasons for patients entered, but not enrolled. 
• 
Total number of patients treated. 
• 
Summary of reasons for patients enrolled, but not treated. 
A detailed summary of reasons for patient discontinuation from study treatment will be 
provided. 
A summary of all identified important protocol violations will be provided. 
8.2.3. Patient Characteristics 
Patient characteristics will include a summary of the following:  
• Patient demographics. 
• Baseline disease characteristics. 
• Pre-existing conditions/secondary conditions. 
• Prior therapy. 
Other patient characteristics will be summarized as deemed appropriate. 
Standard descriptive statistics, such as the mean, median, range and proportion, will be 
used to summarize the patient sample and to estimate parameters of interest. Ninety-five 
percent confidence intervals will be provided for estimates of interest where possible. 
8.2.4. Concomitant Therapy  
A summary of concomitant therapies will be generated in the safety population.  
8.2.5. Treatment Compliance  
Treatment information will be collected at each dose administration. The estimate of 
percent compliance will be given by: 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 97 of 128 
 
    Percent Compliance = Actual dose administered per week   x  100  
 
 
                          Dose expected to be administered per week 
No minimal level of compliance will be defined for patient inclusion in final efficacy 
analysis. In the step 1 analysis it will be necessary that the twelve included patients have 
received at least 80% of the planned dosis. Exploratory analysis of the impact of 
compliance on selected efficacy endpoints may be performed if deemed necessary. 
8.2.6. Efficacy Analyses 
All efficacy definitions are described in section 6.1. 
All efficacy analysis will be based on the Efficacy population. Additional efficacy analyses 
will be performed on the ITT population.  
All primary and secondary endpoints based on radiological (and photographical where 
applicable) assessments of tumour burden (ORR, CBR, RD, PFS, etc.) will be derived 
using the local radiologist’s/investigator’s assessment.   
8.2.6.1. Analyses of Primary Endpoint 
The primary endpoint is ORR 
Objective Response Rate (ORR): A patient will be considered to have achieved an OR if 
the patient has a sustained complete response (CR) or partial response (PR) according to 
RECIST v.1.1 definitions. Otherwise, the patient will be considered as non-responders in 
the ORR analysis. ORR will be estimated by dividing the number of patients with objective 
response (CR or PR) by the Efficacy population (“response rate”).  
Objective Response Rate =   Number of CRs + PRs                       
 Efficacy population  
The ORR will be reported, including a 95% confidence interval. 
These analyses will be conducted at a two-sided 0.05 level of significance.  
The number of responders needed at the end of stage 2 to reject the null hypothesis is at 
least 14 responders. 
Additional sensitivity analyses will be outlined in the SAP. For the analysis in the ITT 
population, patients with inadequate data for tumour assessment (e.g., no baseline 
assessment or no follow-up assessments) will be considered as non-responders in the OR 
rate analysis.  
In addition, the best objective response for each patient will be summarized.  
8.2.6.2. Analysis of Secondary Endpoints 
The secondary efficacy endpoints are: 
Clinical Benefit Rate (CBR): A patient will be considered to have CB if the patient has a 
sustained complete response (CR) or partial response (PR), or stable disease (SD) ≥ 24 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 98 of 128 
 
weeks according to RECIST v.1.1 definitions. Otherwise, the patient will be considered as 
not achieving CB in the CBR analysis.  
CBR will be estimated by dividing the number of patients with CR, PR, or SD ≥ 24 weeks 
by the efficacy population by treatment arm. 
Clinical Benefit Rate = Number of CRs + PRs + SD ≥ 24 weeks                       
   Efficacy population  
The CBR will be reported, including a 95% confidence interval.  
For the CBR analysis in the ITT population, patients with inadequate data for tumour 
assessment (e.g., no baseline assessment or no follow-up assessments) will be considered as 
not achieving CB in the CBR analysis. 
Response Duration (RD): RD data will be censored on the date of the last tumour 
assessment on study for patients who do not have objective tumour progression and who 
have not died due to any cause while on study. Additionally, patients who start a new 
anti-cancer therapy prior to documented PD will be censored at the date of the last tumour 
assessment prior to the start of the new therapy.  
RD will only be calculated for the subgroup of patients with an objective response. 
Progression-Free survival (PFS): PFS data will be censored on the date of the last tumour 
assessment on study for patients who do not have objective tumour progression and who 
have not died due to any cause while on study. Additionally, patients who start a new 
anti-cancer therapy prior to documented PD will be censored at the date of the last tumour 
assessment prior to the start of the new therapy.  
The analyses of PFS will be performed in the ITT and Efficacy populations. PFS time will 
be summarized for the ITT population using the Life tables and displayed graphically 
where appropriate. Confidence intervals (CIs) for the 25th, 50th and 75th percentiles of the 
event free time will be reported.  
Overall Survival (OS): OS data will be censored on the last date the patient is known to be 
alive.  
OS will be analysed in the ITT and Efficacy population. The median event times and 95% 
CIs will be estimated.  
All of the above secondary analyses will be conducted at a two-sided 0.05 level of 
significance.  
The secondary time-to-event endpoints (RD, PFS, OS) will be summarised using a Kaplan-
Meier analysis and associated curves. 
Additional sensitivity analyses will be outlined in the SAP.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 99 of 128 
 
8.2.7. Safety Analyses 
The toxicity and tolerability of study drugs/medications will be evaluated in the safety 
population. Safety analyses will include summaries of the incidence of adverse events by 
maximum NCI-CTCAE grade (v4.0; NCI 2010) that occur during the study treatment 
period or within 30 days of the last dose of study treatment, regardless of causality and 
according to the relationship to study drug/medication as assessed by the Investigator. 
Additionally, the following safety-related outcomes will be summarized: 
• 
Study treatment discontinuations due to adverse events. 
• 
Deaths. 
• 
SAEs and AESIs 
• 
Hospitalizations and transfusions. 
• 
Use of key concomitant medications or growth factors. 
Analyses for data with discrete dates, for example, deaths, transfusions, and concomitant 
medications, will be done through 30 days after each patient’s last dose of study treatment.  
Adverse events will also be analysed in this timeframe; that is, if an event starts within 30 
days of discontinuation from study treatment, but after 30 days after the last dose of study 
treatment, it will not be included. 
Adverse events data and serious adverse events will be presented in frequency tables by 
grade. Haematological and clinical biochemistry toxicities will be assessed from laboratory 
test parameters. The safety analysis will be performed in the safety population.  
8.2.7.1. Other significant adverse events (OAE) 
During the evaluation of the AE data, GEICAM qualified experts will review the list of 
AEs that were neither reported as SAEs nor AESIs. Based on the expert’s judgment, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such.   
A similar review of laboratory, vital signs or ECG data will be performed for identification 
of OAEs. Examples of these are marked haematological and other laboratory abnormalities, 
and certain events that lead to intervention (other than those already classified as serious), 
dose reduction or significant additional treatment. 
There are currently no identified OAEs for olaparib 
8.2.8. BRCA1/2 Methylation and expression analysis 
To explore changes in the methylation status of BRCA1/2 promoter in germline DNA 
prior and after treatment discontinuation. 
The methylation status of the BRCA1 and 2 promoters will be measured in germline DNA 
from blood cells at the beginning of the study and after disease progression or at the end of 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 100 of 128 
 
study treatment for other cause, and in paired primary and metastatic lesions. Methylation 
status will be provided as a continuous (the methylation value will be obtained from the 
average of the CpG dinucleotides included in the sequence analysed) and also as a binomial 
variable (status methylated or not methylated). 
If methylation status is a continuous variable, to compare the value of methylation between 
prior and after treatment, the difference of these values will be used and will be used 
statistical t (student-Fisher) or Wilcoxon test depending if it must be used a parametric or 
non-parametric test. 
If methylation status is a binomial variable, to compare the value of methylation between 
prior and after treatment it will be used the McNemar test or exact binomial test. 
To correlate germline BRCA1/2 methylation data with efficacy parameters: 
To evaluate the effect of methylation status with time to event variables (e.g. PFS, OS) it 
will be used a univariate Cox Regresion model. 
To evaluate the effect of methylation status with efficacy rate parameters it will be used 
chi-square test if both of them are quantitative, and will be used an ANOVA analysis if one 
variable is quantitative and the other one is qualitative. 
To correlate BRCA1/2 methylation between germline and somatic DNA:  
To compare the continuous values of germline and somatic DNA methylation, the 
difference of these values will be used and it will be used statistical t (student-Fisher) or 
Wilcoxon test depending if it must be used a parametric or non-parametric test.  
To correlate BRCA1/2 methylation between primary tumour and metastatic lesions:  
If BRCA1/2 in metastatic lesions is a continuous variable, to compare the value of BRCA1/2 
between primary tumour and metastatic lesions, the difference of these values will be used 
and it will be used statistical t (student-Fisher) or Wilcoxon test depending if it must be 
used a parametric or non-parametric test. 
To correlate BRCA1/2 expression with efficacy parameters:  
mRNA levels of BRCA1 and 2 will be assessed in blood and available tumour samples. 
Expression data will be given as a continuous or as a binomial variable.  
To evaluate the effect of BRCA1/2 expression with time to event variables (PFS, OS) it will 
be used a univariate Cox Regresion model. 
To evaluate the effect of BRCA1/2 expression with efficacy rate parameters it will be used 
chi-square test if both of them are quantitative, and will be used an ANOVA analysis if one 
variable is quantitative and the other one are qualitative. 
To correlate BRCA1/2 expression with BRCA1/2 promoter methylation status:  
We will compare BRCA1/2 expression and BRCA1/2 promoter methylation status when 
they are binary data using chi-square test. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 101 of 128 
 
If methylation status and expression data are given as continuous variables, they will be 
compared using statistical t (student-Fisher) or Wilcoxon test depending if it must be used a 
parametric or non-parametric test.  
If appropriate, additional analysis on all these biomarkers may be performed. More detail of 
all the Analysis of Secondary Endpoints will be described in the SAP.  
8.2.9. Other Analysis 
8.2.9.1. Other Biomarker Analysis 
For baseline continuous endpoint data, descriptive statistics, including the mean, standard 
deviation, median, minimum, and maximum values, will be provided.  
For baseline categorical data, the number and percentage of patients in each category will 
be provided.  
Appropriate statistical methods will be used to investigate any possible relationship of 
biomarker levels with olaparib anti-tumour efficacy. If appropriate, additional exploratory 
analysis on biomarkers may be performed.  
8.2.9.2. Subgroup Analyses  
Exploratory subgroup analysis may be performed if deemed appropriate. 
8.2.10. Interim Analysis 
There is no planned any interim analysis. 
The optimal two stage Simon Model is carried out in two steps. The purposes of the step 1 
analysis is to allow early stopping of the study for futility.  
Following the two-stage Simon design, it will be reviewed whether 4 of the first 12 
evaluable patients show tumour response according to RECIST v.1.1, and if this occurs, 
additional patients will be included to get a total of 34 patients.. If 3 or less than 3 patients 
of the first 12 evaluable patients show an OR, recruitment will be stopped.  
8.2.11. Criteria for End of Study 
This study will be considered complete following the data cut-off date and datalock for the 
final analysis. The data cut-off date for the final analysis will occur after all enrolled 
patients have died or withdraw of the informed consent or there is sufficient data to achieve 
the primary and secondary objectives, whatever occurs first. It is estimated that the final 
analysis could be performed approximately 30 months after the enrolment of the first 
patient because, considering a median OS of 12 months, it is estimated that more than 50% 
of death events will have occurred at that time and overall survival analysis could be 
performed. If further data are collected that are not included as part of the final locked 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 102 of 128 
 
database, the post-lock data will eventually be combined with the locked database and 
stored in a data library separate from the locked database.   
Performing exploratory objectives will be independent of the date of the end of the study. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 103 of 128 
 
9. Informed Consent, Confidentiality, Responsibility Insurance and 
Regulatory Considerations 
9.1. Informed Consent 
The Investigator is responsible for ensuring that the patient understands the risks and 
benefits of participating in the study, including answering any questions the patient may 
have throughout the study and sharing any new information that may be relevant to the 
patient's willingness to continue his or her participation in the trial in a timely manner. 
The informed consent documents will be used to explain the risks and benefits of study 
participation to the patient in simple terms before the patient is entered into the study, and 
to document that the patient is satisfied with his or her understanding of the risks and 
benefits of participating in the study and desires to participate in the study. 
The Investigator is responsible for ensuring that informed consent is given by each patient 
or legal representative. This includes obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior 
to the administration of study drug/medication.   
As used in this protocol, the term "informed consent" includes all consent and assent given 
by patients or their legal representatives. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information, given a copy of the 
revised form and give their consent to continue in the study.  
9.2. Respect of Confidentiality 
The Investigator will be responsible for preserving the suitable information about each patient 
(for example, name, address, telephone number, social security number and study 
identification) so that the competent authorities can have access to said information if 
necessary. These records must be confidentially preserved for the time indicated by the 
legislation. 
The Investigators and GEICAM will maintain the confidentiality of all patients 
participating in the study, according to Good Clinical Practice (GCP) and local legislation. 
The patient data and biological samples collected for the study will be identified through a 
code which will not contain any personal identification and only the study 
doctor/collaborators will be able to link this data with the patient medical history. Access to 
the link between the code and the individual patient will be restricted to IEC, health 
authorities, monitors and auditors of the sponsor or its authorized agents, who are bound to 
secrecy inherent to their profession, when they are required to check the data and study 
procedures to ensure that the study is being done correctly and the data is accurate, but 
always maintaining the confidentiality of the same in accordance with current legislation. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 104 of 128 
 
The patient identity will not be revealed to anyone else except in cases of medical 
emergency or if legally required  
This clinical trial will be held in accordance and in compliance with local current 
legislation. Any treatment of personal data that is held within the clinical trial, for Sponsor, 
Principal Investigator, center and/or any other participant in the clinical trial, especially as 
far as informed consent, shall conform to the provisions of Organic Law 15/1999, of 
December 13, Protection of Personal Data and Royal Decree 1720/2007 of 21 December, 
approving the Regulations implementing the approved law 15/1999, , Regulation (EU) 
2016/679 of the European Parliament and of the Council of 27 April 2016 and any other 
rules in the matter. 
9.3. Responsibility Insurance 
GEICAM has signed an insurance policy to cover the responsibilities of the investigator and 
those of other parties participating in the study in accordance with the current Spanish 
legislation (RD 1090/2015) which regulates clinical trials with medicines in Spain. 
9.4. Regulatory Considerations 
This study will be conducted in accordance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki and with good clinical practices and the 
applicable laws and regulations. The Investigator, head of the medical institution, or 
designee will promptly submit the protocol to applicable ethics committee(s).  
9.4.1. Investigator Information 
Physicians with a specialty in medical oncology will participate as Principal Investigators 
in this clinical trial. 
If investigators are added after the study has been approved by GEICAM, an IEC, or a 
regulatory agency, these additions will not be considered changes to the protocol. 
9.4.2. Protocol Signatures 
After reading the protocol, each Principal Investigator will sign the protocol signature page 
and send a copy of the signed page to GEICAM. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 105 of 128 
 
10. Practical Considerations 
10.1. Monitoring, Audit and Inspections 
Onsite or remote monitoring visits to the study site will be made periodically during the 
study and according to the Monitoring Plan Document to ensure that all aspects of the 
protocol are followed. During the visits to the site, the monitor will review the original 
records of the patients, the records of medication stocks and document preservation. The 
monitor must also evaluate the study procedures and discuss the possible problems with the 
Investigator. During the course of the study, audit visits can be carried out in the participating 
sites. The Investigator will allow direct access to the source documents/data for the tasks of 
monitoring, audit, reviewed by the IEC and the inspection by the Competent Authorities. 
10.2. Preservation of Study Documentation 
The copies of all the relevant information will be preserved by the Investigator for a period of 
at least 25 years after the end of the study according to current legislation. 
10.3. Protocol Modification 
Once it has been authorized by the IEC and the competent authority any protocol 
modification must be documented by writing, in the form of an amendment. 
The amendments must be duly identified, by its chronological order number, dated and 
signed by GEICAM and the Chief Investigator. 
All the protocol substantial amendments must be notified to the IEC involved in the trial, 
the authorization of the involved IEC and/or the competent authority will be necessary 
before their application. 
After reading the protocol amendment, each Principal Investigator will sign the protocol 
amendment signature page and send a copy of the signed page to GEICAM. 
10.4. Study Resources, Use of the Information and Publication 
All the information concerning the study treatment provided by GEICAM in relation to this 
study, and not previously published, is considered to be confidential information with 
property right of GEICAM. This information comprises the basic information about the 
product, the clinical protocol, the work forms where appropriate, the e-CRFs, the assessment 
methods, the technical methodology and the basic scientific data. This confidential 
information will be the property of GEICAM, it must not be disclosed to third parties without 
the prior written consent of GEICAM and it must not be used other than for the purposes of 
the study. 
The information developed during the practice of this clinical study is also considered to be 
confidential. This information can be disclosed to the extent considered necessary by 
GEICAM.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 106 of 128 
 
To allow the use of the information derived from this study and to ensure the compliance 
with the current rules, the Investigator is obliged to provide GEICAM with all the results of 
examinations and all the data developed in this study. Except in that required by law, the 
information obtained during the study can only be provided to the doctors and to the 
competent authorities by GEICAM. 
GEICAM commits to comply with current legislation relating to studies, which establishes 
the obligation to publish the results, both positive and negative, in conferences and 
journals, with reference to IEC that approved the study, and its funding source. The list of 
authors will be developed in accordance with the GEICAM SOPs (standard operating 
procedures). The different disclosures will be decided by the Chief Investigator. By signing 
this protocol, the Chief Investigator and Principal Investigators accept the terms of the 
GEICAM´s publications policy and commit to respect them.  
GEICAM, as sponsor of the study, will assume the funding of the project according to the 
guidelines of this protocol. GEICAM has the support of the company Astrazeneca 
Farmaceutica Spain, S.A. to cover this cost; this support will be independent of the results 
of the study. Additionally, this project will have the support from Centro de Investigación 
Biomédica en Red in the thematic area of Breast Oncology (CIBERONC Breast), of the 
Instituto de Salud Carlos III (ISCIII), in the conduction of the study.   
10.5. Ethics Committee 
The protocol and the informed consent document will be reviewed by the involved IEC. The 
single decision of the IEC referring to the development of the study will be provided in 
writing to GEICAM. 
GEICAM will submit the required reports of the progress of the study to the IEC. At the end 
of the study, GEICAM must inform the IEC of trial closure. 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 107 of 128 
 
11. Important medical procedures to be followed by the investigator 
11.1. Overdose  
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  
Olaparib 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 Tolerated Dose is 300 mg b.i.d. 
(tablet formulation). 
Adverse reactions associated with 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 and on the Overdose CRF information. 
• An overdose without associated symptoms is only reported on the Overdose CRF 
information. 
If an overdose on olaparib occurs in the course of the study and it is associated with an AE 
(serious or not), then Investigators or other site personnel inform appropriate GEICAM 
representatives within one day, i.e., immediately but no later than the end of the next 
business day of when he or she becomes aware of it, using the SAE form. Overdoses 
which are not associated with any AE, can be reported within 30 days. The designated 
GEICAM representative will work with the Investigator to ensure that all relevant 
information is provided.  
When GEICAM has information on overdose, this should also be notified to AstraZeneca. 
11.2. Pregnancy 
All outcomes of pregnancy should be reported to GEICAM. 
11.3. Maternal exposure 
If a patient becomes pregnant during the course of the study olaparib should be 
discontinued immediately. 
The outcome of any conception occurring from the date of the first dose until 1 month after 
the last dose should be followed up and documented. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that olaparib 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 108 of 128 
 
pregnancy, normal birth or congenital abnormality) should be followed up and documented 
even if the patient was withdrawn from the study.  
If any pregnancy occurs in the course of the study, then Investigators or other site personnel 
must inform appropriate GEICAM representatives within one day i.e., immediately but no 
later than the end of the next business day of when he or she becomes aware of it.  
The designated GEICAM representative works with the Investigator to ensure that all 
relevant information is provided within 1 day for SAEs, see Section 6.2.4. and within 30 
days for all other pregnancies. 
The same timelines apply when outcome information is available. 
When GEICAM has information on pregnancies and maternal exposure, this should also be 
notified to AstraZeneca. 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 109 of 128 
 
 
 
 
1 O’Shaughnessy J, Schwartzberg Lee, Danso MA, et al. Phase III Study of Iniparib Plus Gemcitabine and 
Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic Triple-Negative Breast Cancer. 
J Clin Oncol 2014;32(34):3840-3847. 
2 Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with 
BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010 Jul 
24;376(9737):235-44. 
3 Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: 
estimates for 40 countries in 2012. Eur J Cancer. 2013 Apr;49(6):1374-403. 
4 Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality 
Worldwide: IARC 
5 Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. Aug 17, 
2000;406(6797):747-752. 
6 Sorlie T, Perou CM, Tibshirani R, et al.Gene expression patterns of breast carcinomas distinguish tumor 
subclasses with clinical implications. Proc Natl Acad Sci U S A. Sep 11 2001;98(19):10869-10874. 
7 Ocana A, Pandiella A. Identifying breast cancer druggable oncogenic alterations: lessons learned and future 
targeted options. Clin Cancer Res. Feb 15 2008;14(4):961-970. 
8 Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like 
subtype of invasive breast carcinoma. Clin Cancer Res. Aug 15 2004;10(16):5367-5374. 
9 Foulkes W, Smith IE, Reis-Filho JS. Triple Negative Breast Cancer. N Eng J Med 2010;363:1938-1948. 
10 Marotta LL, Almendro V, Marusyk A, et al. The JAK2/STAT3 signaling pathway is required for growth of 
CD44CD24 stem cell-like breast cancer cells in human tumors. J Clin Invest. Jul 1;121(7):2723-2735. 
11 Schneider BP, Winer EP, Foulkes WD, et al. Triple-negative breast cancer: risk factors to potential targets. 
Clin Cancer Res. Dec 15 2008;14(24):8010-8018. 
12 de Rujters TC, Veeck J, de Hoon JPJ, et al. Characteristics of triple-negative breast cancer J Cancer Res 
Clin Oncol 2011;137:183-192. 
13 Chacón RD, Costanzo MV. Triple-negative breast cancer. Breast Cancer Res 2010;12 Suppl 2:S3. 
14 Thike AA, Cheok PY, Jara-Lazaro AR, Tan B, Tan P, Tan PH. Triple-negative breast cancer: 
clinicopathological characteristics and relationship with basal-like breast cancer. Mod Pathol 2010;23(1):123-
33. 
15 Turner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA1 phenotype. Oncogene 2006; 25: 5846–
5853.  
 
 
 
12. References


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 110 of 128 
 
 
 
 
16 Reis-Filho JS and Tutt ANJ. Triple negative tumours: a critical review. Histopathology 2008;52:108–118. 
17 Lakhani SR, van de Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive 
value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2 and p53 in patients 
with mutations in BRCA1 and BRCA2. J Clin Oncol 2002;20:2310-2318. 
18 Joosse SA, Brandwijk KI, Mulder L, et al. Genomic signature of BRCA1 deficiency in sporadic basal-like 
breast tumors. Genes Chromosomes Cancer 2011;50:71-81. 
19 Turner NC, Reis-Filho JS, Russell AM, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. 
Oncogene 2007;26:2126-2132. 
20 Turner NC, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer 
2004;4:814-819. 
21 Lips EH, Mulder L, Oonk A, et al. Triple-negative breast cancer: BRCAness and concordance of clinical 
features with BRCA1-mutation carriers. Br J Cancer 2013;108:2172-2177. 
22 Wood WC, Muss HB, Solin LJ et al. Malignant Tumors of the Breast. In: De Vita VT Jr, Hellmann S, 
Rosenberg SA, editors. Cancer, Principle and Practice of Oncology, 7th Edition, Lippincott Williams and 
Wilkins; 2005; 1415-1477. 
23 Llombart A, de la Haba-Rodríguez J, Ruiz Simón A., et al. SEOM clinical guidelines for the management 
of metastatic breast cancer 2013. Clin Transl Oncol. 2013 Dec;15(12):1004-10 
24 Hudis CA, Gianni L. Triple-negative breast cancer: and unmet medical need. Oncologist 2011;16 Suppl 
1:S1-11. 
25 Rapoport BL, Nayler S, Demetriou GS, et al. Triple-negative breast cancer pathologic diagnosis and current 
chemotherapy treatment options. Oncol Hematol Rev 2014;10(1):25-32. 
26 Wong-Brown MW, Meldrum CJ, Carpenter JE et al. Prevalence of BRCA1 and BRCA2 germline 
mutations in patients with triple-negative breast cancer. Breast Cancer Res Treat. 2015; 15 (epub ahead of 
print). 
27 Bell D, Berchuck A, Birrer M, et al. Cancer Genome Atlas Research N. Integrated genomic analyses of 
ovarian carcinoma. Nature. 2011;474(7353):609-15. 
28 Scully R. Role of BRCA gene dysfunction in breast and ovarian cancer predisposition.Breast Cancer Res. 
2000;2(5):324-30.  
29 Teodoridis JM, Hall J, Marsh S, Kannall HD, Smyth C, Curto J, et al. CpG island methylation of DNA 
damage response genes in advanced ovarian cancer. Cancer Res 2005;65(19):8961-7. 
 
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 111 of 128 
 
 
 
 
30 Catteau A, Harris WH, Xu CF, Solomon E. Methylation of the BRCA1 promoter region in sporadic breast 
and ovarian cancer: correlation with disease characteristics. Oncogene 1999;18(11):1957-65. 
31 Bernal C, Vargas M, Ossandon F, Santibanez E, Urrutia J, Luengo V, et al. DNA methylation profile in 
diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset 
gastric carcinogenesis. Biol Res 2008;41(3):303-15. 
32 Xu X, Gammon MD, Zhang Y, Cho YH, Wetmur JG, Bradshaw PT, et al. Gene promoter methylation is 
associated with increased mortality among women with breast cancer. Breast Cancer Res Treat 
2010;121(3):685-92. 
33 Tapia T, Smalley SV, Kohen P, Munoz A, Solis LM, Corvalan A, et al. Promoter hypermethylation of 
BRCA1 correlates with absence of expression in hereditary breast cancer tumors. Epigenetics 2008;3(3):157-
63. 
34 Wei M, Grushko TA, Dignam J, Hagos F, Nanda R, Sveen L, et al. BRCA1 promoter methylation in 
sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy. 
Cancer Res 2005;65(23):10692-9. 
35 Catteau A, Morris JR. BRCA1 methylation: a significant role in tumor development? Semin Cancer Biol 
2002;12:359-71. 
36 Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedenfalk I, Godwin AK, at al. DNA methylation 
patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 2001;10:3001-7. 
37 Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, et al. Gene-expression profiles in 
hereditary breast cancer. N Eng J Med 2001;344:539-48. 
 
38 Daniels SL, Burghel GJ, Chambers P, Al-Baba S. Connley Daniel D.D, Brock IW, Cramp HE, Dotsenko O, 
Wilks O, Wyld L Cross SS, and Cox A. Levels of DNA Methylation Vary at CpG Sites across the BRCA1 
Promoter, and Differ According to Triple Negative and “BRCA-Like” Status, in Both Blood and Tumour 
DNA. PLoS One. 2016; 11(7): 1-15 
39 Tutt A, Cheang MCU, Kilburn L, et al.  BRCA1 methylation status, silencing and treatment effect in the 
TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or 
recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Abstract S6-01 SABCS  
Cancer Research 77(4 Supplement):S6-01-S6-01 · February 2017. 
40 Van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton 
MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene 
expression profiling predicts clinical outcome of breast cancer. Nature 2002 Jan 31;415(6871):530-6. 
 
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 112 of 128 
 
 
 
 
41 Bell D, Berchuck A, Birrer M, et al. Cancer Genome Atlas Research N. Integrated genomic analyses of 
ovarian carcinoma. Nature. 2011;474(7353):609-15. 
42 Choi JY, James SR, Link PA, McCann SE, Hong CC, Davis W, et al. Association between global DNA 
hypomethylation in leukocytes and risk of breast cancer. Carcinogenesis 2009;30(11):1889–97.   
43 Pal R, Srivastava N, Chopra R, Gochhait S, Gupta P, Prakash N, et al. Investigation of DNA damage 
response and apoptotic gene methylation pattern in sporadic breast tumors using high throughput quantitative 
DNA methylation analysis technology. Mol Cancer 2010;9:303. 
44 Widschwendter M, Apostolidou S, Raum E, Rothenbacher D, Fiegl H, Menon U, et al. Epigenotyping in 
peripheral blood cell DNA and breast cancer risk: a proof of principle study. PLoS One 2008;3(7):e2656. 
45 Bosviel R, Garcia S, Lavediaux G, Michard E. BRCA1 promoter methylation in peripheral blood DNA was 
identified in sporadic breast cancer and controls. Cancer Epidemiology 36 (2012) e177–e182). 
46 Snell C, Krypuy M, Wong EM, Loughrey MB, Dobrovic A. BRCA1 promoter methylation in peripheral 
blood DNA of mutation negative familial breast cancer patients with a BRCA1 tumour phenotype. Breast 
Cancer Res 2008;10(1):R12. 
47 Iwamoto T, Yamamoto N, Taguchi T, Tamaki Y, Noguchi S. BRCA1 promoter methylation in peripheral 
blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation. Breast 
Cancer Res Treat 2010;129(1):69–77. 
48 Snell C, Krypuy M, Wong EM, Loughrey MB, Dobrovic A. BRCA1 promoter methylation in peripheral 
blood DNA of mutation negative familial breast cancer patients with a BRCA1 tumour phenotype. Breast 
Cancer Res 2008;10(1):R12. 
49 Wong EM, Southey MC, Fox SB, Brown MA, Dowty JG, Jenkins MA, Giles GG, Hopper JL, Dobrovic A: 
Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-
associated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 2011, 4(1):23–33. 
50 Al-Moghrabi* N, Nofel A, Al-Yousef N, Madkhali S, Bin Amer SM, Alaiya A, Shinwari Z, Al-Tweigeri T, 
Karakas B, Tulbah A and Aboussekhra A. The molecular significance of methylated BRCA1 promoter in 
white blood cells of cancer-free Females. BMC Cancer 2014, 14:830). 
51 Livraghi L and Garber JE. PARP inhibitors in the management of breast cancer: current data and future 
prospects. BMC Medicine 2015;13:188-204. 
52 Tutt AN, Lord CJ, McCabe N, et al. Exploiting the DNA repair defect in BRCA mutant cells in the design 
of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol 2005;70:139–48. 
53 Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of 
poly (ADP-ribose) polymerase. Nature 2005;434:913–7.  
 
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 113 of 128 
 
 
 
 
54 Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a 
therapeutic strategy. Nature 2005 Apr 14 ;434(7035):917-21. 
55 Fong PC, Boss DS, Yap TA, et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA 
mutation carriers. N Engl J Med 2009;361:123–34. 
56 Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial expansion cohort of the PARP inhibitor veliparib 
(ABT888) and temozolomide in BRCA1/2 associated metastatic breast cancer. Cancer Res 2011;71:P3-16-05. 
57 Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib 
(MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. 
Lancet Oncol. 2013;14:882–92. 
58 De Bono JS, Mina LA, Gonzalez M, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in 
patients with solid tumors. J Clin Oncol. 2013;31:2580.  
59 Kristeleit RS, Burris HA, LoRusso P, et al. Phase 1/2 study of oral rucaparib: final phase 1 results. J Clin 
Oncol. 2014;32:2573. 
60 Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced 
cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244–50. 
61. A Phase III Trial of Niraparib Versus Physician's Choice in HER2 Negative, Germline BRCA Mutation-
positive Breast Cancer Patients (BRAVO) https://clinicaltrials.gov/ct2/show/NCT01905592 
62 Litton JK, Rugo HS, Ettl J, et al Talazoparib in Patients with Advanced Breast Cancer and a Germline 
BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763 
63 Robson M, Im Seock‑Ah, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a 
Germline BRCA Mutation. N Engl J Med 2017; 377:523-533 
64 AbbVie. A phase 3 randomized, placebo-controlled trial of carboplatin and paclitaxel with or without 
veliparib (ABT-888) in HER2-negative metastatic or locally advanced unresectable BRCA-associated breast 
cancer. https://clinicaltrials.gov/ct2/show/NCT02163694.  
65 Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient mammary tumors to the 
PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 
Nov 4;105(44):17079-84. 
66 Hay T, Matthews JR, Pietzka L, et al. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses 
autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with 
carboplatin. Cancer Res. 2009 May 1;69(9):3850-5.  
 
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 114 of 128 
 
 
 
 
67 Moskwa P, Buffa FM, Pan Y, et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and 
sensitivity to PARP inhibitors. Mol Cell. 2011 Jan 21;41(2):210-20.  
68 Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer 
Res. 2012 Nov 1;72(21):5588-99. 
69 Menear KA, Adcock C, Boulter R, et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-
fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med 
Chem 2008:51(20):6581-91. 
70 Narod SA and Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004;4(9):665-76. 
71 Chan KYK, Ozcelik H, Cheung ANY, Ngan HYS, Khoo US. Epigenetic factors controlling the BRCA1 
and BRCA2 genes in sporadic ovarian cancer. Cancer Res 2002:62:4151-4156. 
72 Karch FE and Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol 
Ther 1977; Mar; 21(3):247-54. 




Protocol Attachment 1. Study Schedule 
Study Schedule of Events and Timelines. Protocol GEICAM/2015-06 (COMETA-Breast) 
 
Study Schedule of Events and Timelines. 
GEICAM/2015-06 (COMETA-Breast) 
During Study Treatment. 
During first month: Visits on day 1 and day 8 (+/-3 
days); in subsequent cycles: every 28 days (+/- 7 days),   
Post-treatment 30 days (±7 
days) from the last olaparib 
dose (before starting a new 
anticancer therapyZ) 
After study treatment 
termination 
 
Cycle 
Baseline 
 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Day of cycle 
 
 
1, 8 
1 
1  
 
PFS 
Follow-up 
Period 
(+/- 7 days) 
OS 
Follow-
up Period 
Procedure/Laboratory/  
Diagnostic Test 
Within 28 
daysb 
ENROLMENT 
 
 
 
 
 
 
ICD for Entry (before any study 
specific tests)a 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteriab 
X  
 
 
 
 
 
 
Medical and surgical history and 
demographicsbc 
X (prior to 
sample 
shipment) 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
X 
X 
 
 
ECOG PSb 
X (prior to 
sample 
shipment) 
X 
X 
X 
X 
 
 
Serum or urine pregnancy testb,e 
X (prior to 
sample 
shipment) 
X 
(day 1 pre-dose) 
In the event of a suspected pregnancy 
 
 
Haematologyf 
X 
Xg 
X 
X 
X 
 
 
Coagulation testingh 
X 
If clinically indicated; unless patient is taking warfarin then it is recommended that INR and 
aPTT be monitored at least once per week for the first month, then monthly if the INR is 
stableh 
 
 
Blood Chemistryi 
X 
Xg 
X 
X 
X 
 
 
Urinary testingj 
X 
If clinically indicated  
 
 
Resting 12-lead ECGk 
X 
If clinically indicated   
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 117 of 128 
 
Concomitant medicationsb 
X (prior to 
sample 
shipment) 
X 
 
 
AEs and SAEsl 
X 
X 
 
Olaparib dosingll 
 
X 
X 
X 
 
 
 
Tumour Assessment 
Xm 
Every 8 weeks (+/-1 week) from the start of treatment. 
Responses should be confirmed after 4 weeksm.  
Patients with bone lesions identified at baseline will 
repeat the bone scans if indicatedn.  
 
Xr 
 
Date of death 
 
 
 
 
 
 
Xs 
Biological Samples 
 
 
 
 
Metastatic tissue for central 
determination of BRCA 
methylation and other 
biomarker analysis b,t 
X 
 
 
 
 
 
 
Whole blood for central 
determination of  BRCA 
mutations b,u 
X  
 
 
 
 
 
 
Whole blood for BRCA 
methylation and expression 
analysis and other biomarker 
analysis b,v 
X 
  
 
 
X 
X 
 
Plasma samples for exploratory 
biomarker analysisw 
X 
 
  
X 
(between 
week 4-6) 
 
X 
X 
 
Primary and after progression 
tumour tissue for biomarker 
analysisy 
X 
 
 
 
 
X (if available) 
X (if 
available) 
 
 
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 118 of 128 
 
Study Schedule of Events and Timelines. Protocol GEICAM/2015-06 (COMETA-Breast) 
a 
Signed, written informed consent (approved by IEC) obtained prior to any study specific procedure. 
b 
Some inclusion/exclusion criteria must be checked before sending the tumour and blood samples for BRCA analysis. Refer to Section 4 of the protocol 
for details. To verify these criteria medical history, concomitant medication, ECOG assessment and pregnancy test must be done prior to the shipment 
of the samples to check these inclusion/exclusion criteria 
c 
Includes among others, local laboratory ER/PgR/HER2 expression levels and methods used to assess them, previous treatments, race and age.  
d 
Physical examination includes measurements of blood pressure, pulse rate and body temperature.  
e 
Serum or urine pregnancy test: for pre-menopausal women of childbearing potential one within 28 days prior to the start of study treatment and the 
other on Day 1 of the study prior to commencing treatment.  Tests will be performed by the hospital’s local laboratory.  In the event of a suspected 
pregnancy during the study, the test should be repeated. 
f 
Haematology: Full haematology assessments for safety (haemoglobin, red blood cells, platelets, mean cell volume, mean cell haemoglobin 
concentration, mean cell haemoglobin [MCH], white blood cells, absolute differential white cell count [neutrophils, lymphocytes, monocytes, 
eosinophils and basophils] and absolute neutrophil count or segmented neutrophil count and band forms) at indicated visits and when clinically 
indicated. If treatment is discontinued close to the theoretical date for the next cycle and it is not planned to perform in advance the post-treatment 
visit due to the initiation of a new anticancer therapy, a new haematology analysis should be performed at the moment of the study treatment 
discontinuation.  
Bone marrow or blood cytogenetic analysis may be performed according to standard haematological practice for patients with prolonged 
haematological toxicities as defined in Section 5.4.1.3. Management of Prolonged Haematological Toxicities while on Study Treatment 5.4.1.3. 
Management of Prolonged Haematological Toxicities while on Study Treatment.  
g 
Not on day 1 of cycle 1, if the assessments were performed within the 7 days previous day 1 of treatment. The initiation of the treatment will be within 
7 days after enrolment   
h 
Coagulation testing: Activated partial thromboplastin time (aPTT) and international normalised ratio (INR) will be performed at baseline and if 
clinically indicated unless the patient is receiving warfarin. Patients taking warfarin may participate in this study; however, it is recommended that 
prothrombin time (INR and aPTT) be monitored carefully at least once per week for the first month, then monthly if the INR is stable. 
i 
Blood Chemistry: sodium, potassium, calcium, magnesium, fasting glucose, creatinine, total bilirubin, GGT, AP, AST, ALT, urea or blood urea 
nitrogen (BUN), total protein, albumin and lactic dehydrogenase (LDH) should be performed at indicated visits and when clinically indicated. 
In case a subject shows an AST or ALT ≥ 3 x ULN or total bilirubin ≥ 2 x ULN please refer to Attachment 5 ‘Actions required in cases of combined 
increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions.  
If treatment is discontinued close to the theoretical date for the next cycle and it is not planned to perform in advance the post-treatment visit due to the 
initiation of a new anticancer therapy, a new biochemistry analysis should be performed at the moment of the study treatment discontinuation. 
j 
Urinary testing: Urinalysis by dipstick should be performed at baseline and then only if clinically indicated. Microscopic analysis should be 
performed by the hospital’s local laboratory if required. 
k 
Resting 12-lead ECGs are required within 7 days prior to starting study treatment and when clinically indicated after starting study treatment.  
l 
After informed consent form signature, but prior to initiation of study medications, only SAEs caused by a protocol-mandated intervention will be 
collected. Adverse events to be monitored continuously during the treatment period. All AEs occurring during the study and until the treatment 
discontinuation visit 30 days after the last study medication to be recorded with grading according to NCI-CTCAE, thereafter all study 
drug/medication-related SAEs should continue to be collected.  


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 119 of 128 
 
ll 
Olaparib will be taken orally as a continuous dose every 12h.  
m 
Disease assessment for all patients at baseline will include: 
• 
CT or MRI scan of the chest, abdomen and pelvis (CAP). 
• 
Bone scans will be mandatory if the patient has bone disease or if there is any suspicious of bone metastases. Any suspicious abnormalities (ie, 
hotspots) identified on the bone scans at baseline must be confirmed by X-ray, CT scan with bone windows or MRI. Bone lesions identified at 
baseline will follow the same assessment schedule as for measurable lesions. 
• 
Brain CT or MRI scan is mandatory if the patient has CNS metastases or if there is any suspicious of CNS metastases. 
• 
CT or MRI scan of any other sites of disease as clinically indicated. 
• 
Clinical assessment of superficial disease which will include photographs of all superficial metastatic lesions. 
All lesion measurements must be recorded in the eCRF. Tumour response will be assessed using RECIST v.1.1. every 8 weeks (+/- 1 week). 
n 
Bone scans (if applicable) will be repeated if indicated when complete response is identified in target disease or when progression in bone is 
suspected. Responses should be confirmed according to RECIST v.1.1 after at least 28 days. 
r 
Only to be performed post-study treatment if disease progression has not yet been confirmed and patients have not begun a new therapy, the tumour 
assessment will be performed every 8 weeks from the last tumour assessment.   
s 
The patients will be followed for survival until death, loss to follow-up, withdrawal of consent or study termination by GEICAM. After progression or 
patient is receiving other therapy, the tumour assessment will be performed according to the standard medical practice. The date of death and all 
treatments received by the patient after progression (according to the standard medical practice) will be collected in the eCRF.  
t 
At least one paraffin sample from a metastatic lesion must be sent to the sponsor-designated central laboratory to perform methylation testing and 
other biomarker analysis related to secondary and exploratory objectives. It  is strongly recommended that the metastatic sample has been obtained 
after previous therapy regimen. Surgery blocks or core biopsies would be acceptable, minimal amount of tumour tissue will be specified in the SMM. 
u 
One blood sample (EDTA) to analyse BRCA mutational status must be sent to Myriad laboratories, unless test have been done previously at 
Myriad and absence of mutations has been already determined. It could be sent once signed the ICD 1) in the previous line of treatment, once 
inclusion/exclusion criteria have been reviewed and the patient is considered a potential candidate to the study or 2) after ending the previous line of 
treatment, during screening procedure (see section 6.3 for further instructions). 
v 
Whole blood samples (EDTA and tubes optimized for RNA isolation) will be collected at screening and at the end of treatment to assess germline 
methylation status and/or expression levels of BRCA genes as well as to perform other exploratory analyses. Sample after treatment must be 
taken at the end of study treatment prior to initiation of next therapy regimen. If a patient end the treatment due to other cause different to disease 
progression, collect other sample once progression is documented (although initiated other treatment), if available. 
w 
Plasma samples will be obtained at screening (solicited to all screened patients) and during treatment (one sample taken between 4 to 6 week of 
treatment, preferable prior to receive the treatment) and at the end of study treatment prior to initiation of next therapy regimen (only enrolled 
patients). If a patient end the treatment due to other cause different to disease progression, collect other sample once progression is documented 
(although initiated other treatment), if available.  
y 
Tumour Tissue for Biomarker Assessments: If available, tumour tissue (FFPE) from primary tumour (solicited to all screened patients) and 
metastatic lesions at disease progression (only enrolled patients) will be collected for retrospective biomarker assessments. Samples will be sent to the 
sponsor-designated central laboratories. If a patient end the treatment due to other cause different to disease progression, collect this once progression 
is documented (although initiated other treatment), if available. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 120 of 128 
 
z 
This post-treatment visit must be performed before starting with any new anticancer therapy; however, in case the beginning of this new therapy 
cannot be delayed as per the investigator’s judgment, the safety visit may be performed in advance, but always before starting with the new anticancer 
therapy. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 121 of 128 
 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5(6):649-65. 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 122 of 128 
 
Protocol Attachment 3. Adverse event (AE) non defined in NCI-CTCAE 
 
CTC Grade 
Equivalent to: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily activity. 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no treatment 
or medical intervention is indicated although this could improve the 
overall well-being or symptoms of the patient. 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment or 
medical intervention is indicated in treatment or medical intervention 
is indicated in order to improve the overall well-being or symptoms; 
delaying the onset of treatment is not putting the survival of the 
patient at direct risk. 
Grade 4 
Life-
threatening / 
disabling 
An immediate threat to life or leading to a permanent mental or 
physical conditions that prevents work or performing daily activities; 
treatment or medical intervention is required in order to maintain 
survival.  
Grade 5 
Death 
AE resulting in death. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 123 of 128 
 
Protocol Attachment 4. Adverse Events / Serious Adverse Events 
Assessment Guide 
Time 
After ICD 
Before Drug 
During 
Therapy 
30-Day  
Post-treatment  
Follow-up 
Period 
Long-Term  
Follow-up Period 
Events to 
Collect  
AE/SAEs 
Related 
to 
Procedures 
 
New/Ongoing AE/SAEs 
Regardless of Relatedness to 
Study Treatment or Procedures 
 
New/Ongoing SAEs, including sudden 
death 
of 
unknown 
cause, 
that 
the 
investigators 
considers 
there 
is 
a 
reasonable possibility that the event is 
causally related to the investigational 
product or protocol procedure, even if the 
study has been closed 
 
Any case of MDS/AML or new primary 
malignancy whether it is considered a non-
serious AE [e.g. non-melanoma skin 
cancer] or SAE, and regardless of 
investigator’s assessment of causality 
Abbreviations:  AE = adverse event, ICD = informed consent document, SAE = serious adverse event. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 124 of 128 
 
Protocol Attachment 5. Actions required in cases of combined increase 
of Aminotransferase and Total Bilirubin – Hy’s Law 
TABLE OF CONTENTS  
1. INTRODUCTION  
2. DEFINITIONS 
3. IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
4. FOLLOW-UP  
4.1 Potential Hy’s Law Criteria not met  
4.2 Potential Hy’s Law Criteria met  
5. REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
6. ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA ARE MET 
BEFORE AND AFTER STARTING STUDY TREATMENT (NOT APPLICABLE)  
7. ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW  
8. REFERENCES  
1. INTRODUCTION 
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 GEICAM 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 Product (IMP). 
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. 
2. DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 x ULN and 
Total Bilirubin (TBL) ≥ 2 x ULN at any point during the study irrespective of an increase 
in Alkaline Phosphatase (AP). The elevations do not have to occur at the same time or 
within a specified time frame. 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 125 of 128 
 
Hy’s Law (HL) 
 
AST or ALT ≥ 3 x ULN and TBL ≥ 2 x ULN, where no other reason, other than the IMP, 
can be found to explain the combination of increases, e.g., elevated AP indicating 
cholestasis, viral hepatitis, another drug. The elevations do not have to occur at the same 
time or within a specified time frame. 
3. 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 x ULN 
• 
AST ≥ 3 x ULN 
• 
TBL ≥ 2 x ULN 
The Investigator will without delay review each new laboratory report and if the 
identification criteria are met will: 
• 
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory CRF. 
4. FOLLOW-UP 
4.1 Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
4.2 Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Notify the GEICAM representative who will then inform the central Study Team. 
• 
GEICAM project representatives 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 etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 
• 
Complete the three Liver CRF Modules as information becomes available. 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 126 of 128 
 
• 
If at any time (in consultation with the GEICAM project representatives) the PHL 
case meets serious criteria, report it as an SAE using standard reporting 
procedures. 
5. 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 Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
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 CRF. 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the GEICAM 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 GEICAM 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 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 127 of 128 
 
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review. 
6. ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA ARE 
MET BEFORE AND AFTER STARTING STUDY TREATMENT (NOT 
APPLICABLE) 
7. 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. 
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 
chronic or progressing malignant disease? 
If No: Follow the process described in Section 4.2 of this Appendix. 
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 in Section 4.2 of this 
Appendix. 
* 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 GEICAM clinical project 
representatives if there is any uncertainty. 
8. REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM174090.pdf 
 


GEICAM/2015-06 (COMETA-Breast)                                    
    EudraCT number: 2016-001407-23 
 
Protocol Version 3.0 dated 10-Jun-2019 
 
Confidential                                                                    Page 128 of 128 
 
Protocol Attachment 6. Patient Diary  
In a separate document. 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 1 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
 
 
 
Statistical Analysis Plan (SAP) 
GEICAM/2015-06 
A Phase II Clinical Trial to analyse Olaparib Response in patients with 
BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast 
Cancer “COMETA-Breast study” 
 
 
 
Sponsor: GEICAM (Spanish Breast Cancer Research Group Foundation) 
Chief Investigator:  
Dr. Juan R. de la Haba-Rodríguez,  
Instituto Maimónides de Investigación Biomédica (IMIBIC) 
 
 Hospital Universitario Reina Sofía; Córdoba, Spain  
Author: María José Escudero 
Version: 1.0 
Date: 22 September 2020 
CONFIDENTIAL 
The information and data included in this Statistical Analysis Plan contain secrets and privileged or confidential 
information which is the property of GEICAM. No one is authorized to make this information public without the written 
permission of GEICAM. These limitations shall also be applied to all the information considered to be privileged or 
confidential and provided in the future. This material can be disclosed and used by its equipment and collaborators as 
necessary for conducting the clinical trial. 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 2 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
 
 
Protocol No.: GEICAM/2015-06 
 
Protocol title: A Phase II Clinical Trial to analyse Olaparib Response in patients with BRCA1 
and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer”. “COMETA-Breast study. 
 
Protocol Version: 3.0 10 June 2019 
 
Sponsor:  GEICAM 
 
This Statistical Analysis Plan was created according the ICH Good Clinical Practice (1) (2), 
GEICAM policies and Standard Operating Procedures (SOP); and is consistent with the study 
protocol (3). 
 
 
Version Date: : 22-Sep-20 
 
 
Version No.: 1 
 
 
Previous Version: NA 
 
 
   
 
Prepared by Statistician: 
 
 
 
 
 
 
María José Escudero 
 
_______________________ 
 
_______________________ 
Name 
Signature 
Date 
 
 
 
 
Reviewed by: 
 
 
 
 
 
Statistician 
 
 
Juan José Miralles 
 
 
_______________________ 
 
_______________________ 
Name 
Signature 
Date 
 
 
 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 3 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
Project Manager 
 
 
 
NA 
 
_______________________ 
 
_______________________ 
Name 
Signature 
Date 
 
Translational Project Manager  
 
 
 
 
Nuria Martín  
 
 
 
_______________________ 
 
 
______________________ 
Name 
Signature 
Date 
(project manager until March 
2018 and current PM back up) 
 
 
 
 
Approved by: 
 
 
 
 
 
Medical Monitor 
 
Susana Bezares 
 
 
 
______________________ 
 
 
______________________ 
Name 
Signature 
Date 
 
 
 
 
Chief Investigator 
 
Dr. Juan R. de la Haba-
Rodríguez 
 
 
 
 
______________________ 
 
 
 
_______________________ 
Name 
Signature 
Date 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 4 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION .................................................................................................... 8 
2. 
STUDY OBJECTIVES ............................................................................................ 8 
2.1 
Main Objective ............................................................................................... 8 
2.2 
Secondary Objective...................................................................................... 8 
2.3 
Exploratory Objectives ................................................................................... 9 
3. 
STUDY DESIGN .................................................................................................... 9 
3.1 
Sample Size ................................................................................................ 10 
3.2 
Randomization............................................................................................. 11 
4. 
STUDY POPULATION ......................................................................................... 11 
4.1 
ITT Population ............................................................................................. 11 
4.2 
Efficacy population ...................................................................................... 11 
4.3 
Safety population ......................................................................................... 11 
4.4 
Biomarker population ................................................................................... 11 
4.5 
Discontinuations .......................................................................................... 11 
4.5.1 
Discontinuation of Study Drug/Medication ...................................... 11 
4.5.2 
Discontinuation of Study Sites ........................................................ 12 
4.5.3 
Discontinuation of Study ................................................................. 13 
5. 
STUDY VARIABLES ............................................................................................ 13 
5.1 
Patient Disposition ....................................................................................... 13 
5.2 
Patient Characteristics ................................................................................. 13 
5.3 
Concomitant Therapy .................................................................................. 14 
5.4 
Treatment Compliance ................................................................................ 14 
5.5 
Other Variables ............................................... ¡Error! Marcador no definido. 
6. 
ENDPOINTS ........................................................................................................ 14 
6.1 
Efficacy Endpoints ....................................................................................... 14 
6.1.1 
Primary End-point ........................................................................... 14 
6.1.2 
Secondary End-points .................................................................... 14 
6.2 
Exploratory End-points ................................................................................ 15 
7. 
DATA SCREENING AND ACCEPTANCE. ........................................................... 15 
7.1 
Missing data ................................................................................................ 16 
7.1.1 
Missing date ................................................................................... 16 
7.2 
Statistical software ....................................................................................... 16 
7.3 
Database lock .............................................................................................. 16 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 5 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
8. 
INTERIM ANALYSIS ............................................................................................ 16 
8.1 
Purpose of interim analysis .......................................................................... 17 
8.2 
IDMC (Interim Data Monitoring Committee) ................................................. 17 
9. 
STATISTICAL METHODS ANNALYSES .............................................................. 17 
9.1 
Statistical Methods ...................................................................................... 17 
9.2 
Statistical analyses ...................................................................................... 18 
9.2.2 
Safety Analyses .............................................................................. 20 
9.2.3 
BRCA1/2 Methylation and expression analysis ............................... 22 
9.2.4 
Other Analyses ............................................................................... 23 
9.2.5 
Other Subgroup Analyses ............................................................... 23 
9.2.6 
Second Course Phase Analyses ..................................................... 24 
10. 
TABLES Y FIGURES ........................................................................................... 24 
11. 
APPENDIX (if applicable) ..................................................................................... 28 
12. 
BIBLIOGRAFHY /REFERENCES ......................................................................... 28 
13. 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ................................... 28 
  
 
 
 
 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 6 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
ABBREVIATIONS AND DEFINITIONS 
 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AML 
Acute Myeloid Leukaemia 
BC 
Breast Cancer 
BRCA1 
Breast Cancer type 1 
BRCA2 
Breast Cancer type 2 
CB 
Clinical Benefit 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CpG 
5'—C—phosphate—G—3'  
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
ECG  
Electrocardiography 
eCRF 
Electronic Case Report Form (sometimes referred to as Clinical Report Form). 
An electronic form for recording study participants’ data during a clinical study, 
as required by the protocol. 
GCP 
Good Clinical Practice 
GEICAM 
Spanish Breast Cancer Group 
ICF  
Informed Consent Form 
IDMC 
Interim Data Monitoring Committee 
IEC 
Independent Ethics Committee 
ITT 
Intent To Treat 
MDS 
Myelodysplastic Syndrome  
MDS/AML 
Myelodysplastic Syndrome/Acute Myeloid Leukaemia  
NCI 
National Cancer Institute 
NGS panel Next Generation Sequencing panel 
OAE 
Other significant Adverse Events  
OR 
Objective Response 
ORR 
Objective Response Rate 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 7 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
OS 
Overall Survival 
PARP  
Enzyme Poly ADP Ribose Polymerase 
PD 
Progressive Disease or Programmed Death depending on the context 
PFS 
Progression-Free Survival 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
TLFs 
Tables, Listings and Figures 
TN 
Triple-Negative 
TNBC 
Triple-Negative Breast Cancer  
 
 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 8 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to give a detailed description of the statistical 
analyses to be performed to generate the final report for GEICAM/2015-06 study (COMETA-
Breast). 
Based on published data included in the protocol and data from the full clinical program to date, it is 
anticipated that olaparib, an orally active inhibitor of the enzyme poly ADP ribose polymerase 
(PARPi), will have a positive benefit risk profile for the treatment of the minority well-defined 
population of advanced triple-negative breast cancer (TNBC) patients with the promoter 
methylation of BRCA genes. 
The statistical analyses of this study will be the responsibility of GEICAM. The interpretation of 
these results will be the responsibility of the Chief Investigator of the study.   
This document may modify the plans outlined in the protocol; however, any major modifications of 
the primary endpoint definition and/or its analysis will also be reflected in a protocol amendment. 
All analyses will be performed using the SAS Enterprise Guide 5.1 version. 
 
2. 
STUDY OBJECTIVES 
2.1 
Main Objective 
• 
To analyse the olaparib efficacy in the treatment of patients diagnosed of advanced TNBC 
with BRCA1 and/or BRCA2 promoter methylation assessed in somatic DNA. 
2.2 
Secondary Objectives 
• 
To analyse other efficacy measures. 
o Clinical Benefit Rate (CBR). 
o Duration of Response (DoR). 
o Progression Free Survival (PFS). 
o Overall Survival (OS). 
• 
To analyse olaparib safety.  


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 9 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
• 
To explore changes in the methylation status of BRCA1/2 promoter in germline DNA prior 
and after treatment discontinuation for any reason and correlate germline BRCA1/2 
methylation data with efficacy parameters. 
• 
To correlate BRCA1/2 methylation between germline and somatic DNA and between 
primary tumour and metastatic lesions.  
• 
To correlate BRCA1/2 expression with methylation status of BRCA1/2 promoter and 
efficacy parameters.   
2.3 
Exploratory Objectives 
• 
Explore biomarkers of clinical activity in tumour and blood samples. 
3. 
STUDY DESIGN 
This is a multicenter, non-randomised, phase II clinical trial to assess the efficacy and safety of 
olaparib in monotherapy in patients diagnosed of advanced TNBC with methylation of BRCA1 
and/or 2 promoters (assessed in DNA from metastatic lesions) and absence of BRCA1 and 2 
germline mutations. Patients must have received at least one previous regimen in the advance 
disease setting.  
 
Figure 1 Study Design 
 
  
Potential eligible patients will be screened to assess germinal (g) BRCA mutational status at Myriad 
laboratory (unless the BRCA mutational status is already known based on a Myriad previous 
report).  
Blood samples for mutational BRCA screening could be sent either 1) during the previous line of 
treatment, once the eligibility criteria have been reviewed and the patient is considered a potential 
candidate for the study (at least the patient must have measurable and biopsiable disease) or 2) 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 10 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
after end of the line of treatment prior to study enrolment (simultaneously to the shipment of the 
tumour samples for methylation analysis). A specific Informed Consent Form (ICF) must be signed 
for this screening assessment. 
Somatic (s) BRCA promoter methylation will be assessed also centrally at an external reference 
central laboratory selected by GEICAM. Tumour samples must proceed from a metastatic lesion, it 
is strongly recommended to obtain it after the line treatment immediately previous to the study 
entry. 
Patients with a positive methylation status on BRCA1 and/or BRCA2 and lacking of known 
deleterious or suspected deleterious mutations in both genes could be included in the study to 
receive olaparib tablet formulation at 600 mg daily dose (given in two oral administrations of 300 
mg every 12 hours approximately). Blood and tumour samples collected from all registered patients 
could be used for the secondary and exploratory analyses of the study, including but not limited to 
the assessment of germline methylation status and gene expression levels of BRCA1/2. 
Patients will continue to receive their treatment until objective disease progression, symptomatic 
deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first.  
Each assessment of tumour response will be performed as scheduled according to the calendar 
regardless of any dosing delay to prevent the introduction of bias into the assessment of efficacy.  
According to RECIST v.1.1 in case of patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time every 
effort should be made to document objective progression, even after discontinuation of treatment. 
The objective response status of such patients should be determined considering RECIST v.1.1 
instructions. In case any efficacy assessment cannot be done, they will be considered not 
evaluable for response rate analysis and PFS will be censored at the date of the last tumour 
assessment.  
3.1 
Sample Size 
We have set the null hypothesis (H0) that ORR will be 30% (ORR achieved by TN patients treated 
with gemcitabine plus carboplatini) versus the alternative hypothesis (H1) that ORR will be 54% 
(ORR showed by TN BRCA mutated patients treated with olaparibii). Using an optimal two-stage 
Simon model and considering an alpha error of 0.05 and a statistical power of 80%, it will be 
required to include 31 evaluable patients. Twelve evaluable patients will be enrolled in the first 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 11 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
stage, and if at least 4 patients of them have response, additional patients will be recruited to get a 
total of 31 evaluable patients. Assuming a 10% dropout rate, the total number of patients to be 
enrolled is 34. Considering, these data the number of responders needed at the end of stage 2 to 
reject the null hypothesis is at least 14 responders. 
3.2 
Randomization 
Not applicable. 
4. 
STUDY POPULATION 
4.1 
ITT Population 
The Intent to treat population (ITT) will include all patients who are enrolled in the study.  
4.2 
Efficacy population 
A subset of the ITT population that have received at least one dose of study medication and has 
performed at least one tumour response assessment according to RECIST version 1.1 (unless PD, 
death or unacceptable toxicity is observed before the first tumour response assessment) and 
without major protocol deviations according to the protocol deviation manual. 
4.3 
Safety population 
Safety population will include all patients who are enrolled and have received at least one dose of 
the study treatment. This population is for the safety analysis.      
4.4 
Biomarker population 
A subset of enrolled patients with evaluable blood and/or tumour samples required for achievement 
of the secondary and exploratory objectives of the study.  
 
4.5 
Discontinuations 
4.5.1 
Discontinuation of Study Drug/Medication 
The criteria for enrolment must be followed explicitly. If a patient who does not meet enrolment 
criteria is inadvertently enrolled, that patient should be discontinued from the study 
drugs/medications, but can be allowed to continue in the study in order to provide the follow-up 
data needed for the analysis of the entire population. An exception may be granted if the patient, in 
the opinion of the Investigator, is having benefit from the study drugs/medications. In these rare 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 12 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
cases, the investigator must obtain documented approval from GEICAM to allow the patient to 
continue to receive the study drugs/medications. 
Patients can be discontinued from the study therapy in the following circumstances: 
• Patient’s own request. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. 
• Unacceptable toxicity as defined in the protocol. 
• Any clinical adverse event (AE), laboratory abnormality or inter-current illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the patient. 
• Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukaemia (AML).  
• Pregnancy: 
✓ Instruct to contact the investigator or study staff immediately if they suspect they might 
be pregnant. 
✓ The investigator must immediately notify GEICAM if a study patient becomes pregnant. 
• Tumour progression as defined in the protocol. 
• Severe non-compliance with the study protocol by the patient. 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for 
treatment of either a psychiatric or physical (e.g. infectious disease) illness. 
• Physician’s decision, including need of other anti-cancer therapy, not specified in the 
protocol.  
• Termination of the study by GEICAM. 
All permanent treatment discontinuation should be recorded by the Investigator in the eCRF when 
considered as confirmed. 
It is important to discriminate between discontinuation of study treatment only and withdrawal from 
study (study treatment and follow up). 
4.5.2 
Discontinuation of Study Sites 
Study Site participation may be discontinued if GEICAM, the investigator or the Independent Ethics 
Committee (IEC) of the study site judges it necessary for any reason.  


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 13 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
4.5.3 
Discontinuation of Study 
The study may be discontinued by GEICAM if this is medically reasonable and consistent with 
applicable regulations of Good Clinical Practice (GCP). Stopping the study for medical reasons 
may be required if patients experienced adverse reactions under the treatment with the study 
drug/medication or if new information about the safety or effectiveness of the study drug/medication 
justifies it. 
5. 
STUDY VARIABLES 
5.1 
Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
• 
Summary of patients entered and by site. 
• 
Total number of patients entered. 
• 
Total number of patients enrolled and by site. 
• 
Summary of reasons for patients entered, but not enrolled. This summary will include: 
o Nº of patients not included due to having BRCA1/2 germline mutations 
o Nº of patients not having methylated BRCA1and/or BRCA2  promoters  
o Nº of patients not having tumor available 
o Nº of patients in which the  methylation or germline mutation analysis was not 
assessable. 
 
• 
Total number of patients treated and by site.  
• 
Summary of reasons for patients enrolled, but not treated.  
A detailed summary of reasons for patient discontinuation from study treatment will be provided. 
A summary of all identified important protocol major violations will be provided. 
 
5.2 
Patient Characteristics 
Patient characteristics will include a summary of the following:  
• 
Patient demographics. 
• 
Baseline disease characteristics. 
• 
Pre-existing conditions/secondary conditions. 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 14 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
• 
Prior anti-cancer therapy. 
Other patient characteristics will be summarized as deemed appropriate. 
Standard descriptive statistics, such as the mean, median, range and proportion, will be used to 
summarize the patient sample and to estimate parameters of interest. Ninety-five percent 
confidence intervals will be provided for estimates of interest where possible.  
5.3 
Concomitant Therapy 
A summary of concomitant therapies will be generated in the safety population.  
5.4 
Treatment Compliance 
Treatment information will be collected at each dose administration. The estimate of percent 
compliance will be given by: 
 
𝑃𝑒𝑟𝑐𝑒𝑛𝑡 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=
𝐴𝑐𝑡𝑢𝑎𝑙 𝑑𝑜𝑠𝑒 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 𝑝𝑒𝑟 𝑤𝑒𝑒𝑘
𝐷𝑜𝑠𝑒 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑡𝑜 𝑏𝑒 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 𝑝𝑒𝑟 𝑤𝑒𝑒𝑘× 100 
 
No minimal level of compliance will be defined for patient inclusion in efficacy analyses. To be 
considered compliant patients should have received at least 80% of the planned number of doses. 
Exploratory analysis of the impact of compliance on selected efficacy endpoints may be performed 
if deemed necessary. 
 
6. 
ENDPOINTS  
6.1 
Efficacy Endpoints 
6.1.1 
Primary End-point 
Objective Response Rate (ORR) defined as Complete Response (CR) plus Partial Response 
(PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. 
 
6.1.2 
Secondary End-points 
The following secondary end-points will be studied: 
• 
Clinical Benefit Rate (CBR), Duration of Response (DoR), Progression Free Survival (PFS) 
and Overall Survival (OS). 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 15 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
• 
Adverse events defined by the NCI-CTCAE (National Cancer Institute Common 
Terminology Criteria for Adverse Events) version 4.0. 
• 
The methylation status of BRCA 1 and 2 promoters will be measured in germline DNA from 
blood cells at the beginning of the study and after PD, or at the end of study treatment by 
other reason, and in paired primary and metastatic lesions. It will be analysed: 1) changes 
of germline methylation pre- and post-treatment; 2) correlation between germline 
methylation status and efficacy outcome data; 3) correlation between germline and somatic 
methylation status and 4) correlation between primary and metastatic lesions.  
6.2 
Exploratory End-points 
The following exploratory end-points could be studied: 
• 
Biomarker values from the primary or metastatic tumour tissue could be used for 
assessment of biomarkers related to breast tumour sensitivity and/or resistance to olaparib 
(e.g. may include but not limited to somatic BRCA1/2 mutational status or other genes 
related to cancer susceptibility or thought to be related to the drug mechanism of action). 
These samples will be instrumental to explore biomarkers of response or resistance to 
olaparib.  
• 
DNA and RNA obtained from the blood samples collected during the study may be used for 
potential pharmacogenomics analyses related to drug response or adverse drug reactions 
(including but not limited to comparison of germline DNA or RNA patterns of patients who 
respond well and those who respond poorly to treatment). For example, genes coding drug 
metabolizing enzymes, drug transport proteins or genes involved in DNA repair pathways, 
cancer susceptibility or thought to be related to the drug mechanisms of action may be 
analysed.  
• 
Specific mutations or epigenetic biomarkers identified in pre-therapy tumour specimens as 
potentially linked to treatment response could be tested in plasma DNA. A targeted NGS 
panel may be designed to study all the candidate mutations. Plasma DNA has also the 
potential to be a surrogate of tumour load and may also be instrumental to monitor disease.  
7. 
DATA SCREENING AND ACCEPTANCE. 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 16 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
7.1 
Missing data 
The frequency of missing data will be examined and reported for each variable in the analysis. We 
will not perform data imputation for missing data. 
7.1.1 
Missing date 
If the day of the month is missing for any date used in a calculation, the 15th of the month will be 
used to replace the missing date unless the calculation results in a negative time duration (e.g., 
date of onset cannot be prior to day one date). In this case, the date resulting in 1 day duration will 
be used. If the day of the month and the month are missing for any date used in a calculation, the 
date will be considered missing. 
7.2 
Statistical software 
The statistical analysis will be developed in SAS Enterprise Guide v7.1. 
7.3 
Database lock 
The first database lock will be carried out when enough data have been obtained to perform the 
step 1 analysis of the optimal two stage Simon model. 
The database lock for efficacy analysis will be carried out when there will be sufficient data to 
achieve the primary and secondary objectives or at the date of last patient´s death or withdraw of 
the informed consent, whichever comes first. As the study design is two Stage Simon design, if in 
step 1 we do not obtain the enough responses the data base will be closed and perform the 
primary analysis.  
 
8. 
INTERIM ANALYSIS 
There is no planned any interim analysis. 
 
The optimal two stage Simon Model is carried out in two steps. The purposes of the step 1 analysis 
are to allow early stopping of the study for futility.  
 
Following the two-stage Simon design, it will be reviewed whether if at least 4 of the first 12 
evaluable patients show tumour response according to RECIST version 1.1, and if this occurs, 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 17 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
additional patients will be included to get a total of 34 patients. If 3 or less patients of the first 12 
evaluable patients show an OR, recruitment will be stopped. 
In case of recruitment is stopped after the step 1, it will be reviewed the feasibility and interest of 
performing some of the described secondary and exploratory analysis based on the available 
number of patients and samples.  
 
8.1 
Purpose of interim analysis 
Not applicable. 
8.2 
IDMC (Interim Data Monitoring Committee) 
Not applicable. 
 
 
9. 
STATISTICAL METHODS ANNALYSES 
9.1 
Statistical Methods 
For descriptive analyses, frequencies, percentages and ninety-five percent confidence intervals of 
interest will be calculated for categorical variables wherever possible. For continuous variables, 
standard descriptive statistics, such as total number of observations, number of available data, 
mean, standard deviation, minimum, percentile 25, median, percentile 75 and maximum will be 
calculated. 
For efficacy analyses the 2-sided 95% confidence interval will be presented wherever possible. A 
bilateral (2-sided) 5% significance level will be used to assess the statistical significance. 
Chi-square χ2 test or Fisher exact test will be used to explore the relationship between two 
qualitative variables. Mann-Whitney-Wilcoxon test will be used to compare a quantitative variable in 
two independent groups. 
Logistic regression models will be used to test the association of co-variables with a binary variable 
(ORR, CBR) and to estimate odds ratios and their 95% confidence intervals. 
Kaplan-Meier Method will be used to estimate the survival function, survival median and 
probabilities of occurrence of event at a certain point of time. 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 18 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
Cox Proportional Hazards Regression Model will be used to estimate the hazard ratio and assess 
the association between several risk factors, considered simultaneously, and survival time (PFS, 
RD, OS). 
 
9.2 
Statistical analyses 
An exploratory and descriptive analysis will be developed for each variable in the study. All 
continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, standard deviation, maximum and minimum and confidence interval (CI) will be 
performed when this information is considered relevant to describe a unique variable. The 
frequency and percentages of observed levels will be reported for all categorical measures. 
Ninety-five percent confidence intervals will be provided for estimates of interest wherever 
possible.  
All statistical tests will be performed with a significance level of 5%, unless otherwise specified. For 
qualitative comparison of independent samples the Chi-squared test (or Fisher's exact test for 2x2 
tables) will be used, while for the quantitative samples Mann-Whitney-U will be used. Logistic 
regression models will be used to test the association of covariables with objective response 
(yes/no) and clinical benefit (yes/no), and to estimate odds ratios and their 95% confidence 
intervals. The Kaplan-Meier limit-product method will be used to estimate PFS and OS. The 
Kaplan-Meier survival curve will be presented graphically. Median PFS and OS with the 95% 
confidence interval will be reported. Cox regression models will be used to estimate hazard ratios 
and its 95% confidence interval. The Wald test will be used to establish the prognostic importance 
of each covariable.  
All efficacy analyses will be based on the Efficacy population. Additional efficacy analyses will be 
performed on the ITT population.  
All primary and secondary endpoints based on radiological (and photographical where applicable) 
assessments of tumor burden (PFS, ORR, CBR and RD) will be derived using the local 
radiologist’s/investigator’s assessment.   
9.2.1.1 Analyses of Primary Endpoint 
The primary endpoint is ORR. 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 19 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
Objective Response Rate (ORR): A patient will be considered to have achieved an objective 
response (OR) if the patient has a complete response (CR) or partial response (PR) according to 
RECIST version 1.1 (4) definitions. Otherwise, the patient will be considered as non-responder in 
the ORR analysis. ORR will be estimated by dividing the number of patients with objective 
response (CR or PR) by the Efficacy population (“response rate”).  
 
𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑅𝑎𝑡𝑒= 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐶𝑅𝑠+ 𝑃𝑅𝑠
𝐸𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑃𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 
 
The ORR will be reported, including a 95% confidence interval using the Clopper-Pearson method 
(5). 
These analyses will be conducted at a two-sided 0.05 level of significance.  
The number of responders needed at the end of stage 2 to reject the null hypothesis is at least 14 
responders. 
Additional sensitivity analyses will be done with the ITT population. For the analysis in the ITT 
population, patients with inadequate data for tumour assessment (e.g., no baseline assessment or 
no follow up assessments) will be considered as non-responders in the ORR analysis.  
In addition, the best objective response (BOR) for each patient will be summarized. 
9.2.1.2 Analysis of Secondary Endpoints 
 
The secondary efficacy endpoints are: 
Clinical Benefit Rate (CBR): A patient will be considered to have CB if the patient has a sustained 
complete response (CR) or partial response (PR), or stable disease (SD) ≥ 24 weeks according to 
RECIST version 1.1 definitions. Otherwise, the patient will be considered as not achieving CB in 
the CBR analysis.  
CBR will be estimated by dividing the number of patients with CR, PR, or SD ≥ 24 weeks by the 
efficacy population. 
 
𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐵𝑒𝑛𝑒𝑓𝑖𝑡  𝑅𝑎𝑡𝑒= 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐶𝑅𝑠+ 𝑃𝑅𝑠+ 𝑆𝐷≥24 𝑤𝑒𝑒𝑘𝑠
𝐸𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑃𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛
 
 
The CBR will be reported, including a 95% confidence interval.  


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 20 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
For the CBR analysis in the ITT population, patients with inadequate data for tumour assessment 
(e.g., no baseline assessment or no follow-up assessments) will be considered as not achieving 
CB in the CBR analysis. 
Duration of Response (DoR): DoR is defined as the time from the first documentation of objective 
tumour response (CR or PR) to the first documented PD using RECIST version 1.1, or to death due 
to any cause, whichever occurs first. DoR data will be censored on the date of the last tumour 
assessment on study for patients who do not have objective PD and who have not died due to any 
cause while on study. Additionally, patients who start a new anti-cancer therapy prior to 
documented PD will be censored at the date of the last tumour assessment prior to the start of the 
new therapy.  
RD will only be calculated for the subgroup of patients with an objective response. 
Progression-Free survival (PFS): PFS is defined as the time from study enrolment to the first 
documented PD, using RECIST version 1.1, or death from any cause, whichever occurs first. PFS 
data will be censored on the date of the last tumour assessment on study for patients who do not 
have objective PD and who have not died due to any cause while on study. Additionally, patients 
who start a new anti-cancer therapy prior to documented PD will be censored at the date of the last 
tumour assessment prior to the start of the new therapy.  
The analyses of PFS will be performed in the ITT and Efficacy populations. PFS time will be 
summarized for the ITT population using the Life tables and displayed graphically where 
appropriate. Confidence intervals (CIs) for the 25th, 50th and 75th percentiles of the event free time 
will be reported.  
Overall Survival (OS): OS is defined as the time from the date of study enrolment to the date of 
death from any cause. OS data will be censored on the last date the patient is known to be alive.  
OS will be analysed in the ITT and Efficacy population. The median event times and 95% CIs will 
be estimated.  
All of the above secondary analyses will be conducted at a two-sided 0.05 level of significance.  
The secondary time-to-event endpoints (RD, PFS, OS) will be summarised using a Kaplan-Meier 
analysis and associated curves. 
 
9.2.2 
Safety Analyses 
The toxicity and tolerability of study drugs/medications will be evaluated in the safety population. 
Safety analyses will include summaries of the incidence of adverse events (AEs) by maximum NCI-


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 21 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
CTCAE grade (v4.0; NCI 2010) that occur during the study treatment period or within 30 days of 
the last dose of study treatment, regardless of causality and according to the relationship to study 
drug/medication as assessed by the Investigator. Additionally, the following safety-related 
outcomes will be summarized: 
• 
Study treatment discontinuations due to AEs. 
• 
Deaths. 
• 
SAEs and AESIs. 
• 
Hospitalizations and transfusions. 
• 
Use of key concomitant medications or growth factors. 
Analyses for data with discrete dates, for example, deaths, transfusions, and concomitant 
medications, will be done through 30 days after each patient’s last dose of study treatment.  
Adverse events will also be analysed in this timeframe; that is, if an event starts within 30 days of 
discontinuation from study treatment, but after 30 days after the last dose of study treatment, it will 
not be included. 
Adverse events and SAEs data will be presented in frequency tables by grade. Haematological and 
clinical biochemistry toxicities will be assessed from laboratory test parameters. The safety 
analyses will be performed in the safety population.  
 
9.2.2.1 Other significant adverse events (OAE) 
During the evaluation of the AE data, GEICAM qualified experts will review the list of AEs that were 
neither reported as SAEs nor AESIs. Based on the expert’s judgment, significant AEs of particular 
clinical importance may, after consultation with the Global Patient Safety Physician of AstraZeneca, 
be considered OAEs and reported as such.   
A similar review of laboratory, vital signs or ECG data will be performed for identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction or 
significant additional treatment. 
There are currently no identified OAEs for olaparib. 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 22 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
9.2.3 
BRCA1/2 Methylation and expression analysis 
To explore changes in the methylation status of BRCA1/2 promoter in germline DNA prior 
and after treatment discontinuation. 
The methylation status of the BRCA1 and 2 promoters will be measured in germline DNA from 
blood cells collected at the beginning of the study and after disease progression or at the end of 
study treatment for other cause, and in paired primary and metastatic lesions. Methylation status 
will be provided as a continuous (the methylation value will be obtained from the average of the 
CpG dinucleotides included in the sequence analysed) and also as a binomial variable (status 
methylated or not methylated). 
If methylation status is a continuous variable, to compare the value of methylation between prior 
and after treatment, the difference of these values will be used and will be used statistical t 
(student-Fisher) or Wilcoxon test depending if it must be used a parametric or non-parametric test. 
If methylation status is a binomial variable, to compare the value of methylation between prior and 
after treatment it will be used the McNemar test or exact binomial test. 
To correlate germline BRCA1/2 methylation data with efficacy parameters: 
To evaluate the effect of methylation status with time to event variables (e.g. PFS, OS) it will be 
used a univariate Cox Regresion model. 
To evaluate the effect of methylation status with efficacy rate parameters it will be used chi-square 
test if both of them are quantitative, and will be used an ANOVA analysis if one variable is 
quantitative and the other one is qualitative. 
To correlate BRCA1/2 methylation between germline and somatic DNA:  
To compare the continuous values of germline and somatic DNA methylation, the difference of 
these values will be used and it will be used statistical t (student-Fisher) or Wilcoxon test 
depending if it must be used a parametric or non-parametric test.  
To correlate BRCA1/2 methylation between primary tumour and metastatic lesions:  
If BRCA1/2 in metastatic lesions is a continuous variable, to compare the value of BRCA1/2 
between primary tumour and metastatic lesions, the difference of these values will be used and it 
will be used statistical t (student-Fisher) or Wilcoxon test depending if it must be used a parametric 
or non-parametric test. 
To correlate BRCA1/2 expression with efficacy parameters:  


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 23 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
mRNA levels of BRCA1 and 2 will be assessed in blood and available tumour samples. Expression 
data will be given as a continuous or as a binomial variable.  
To evaluate the effect of BRCA1/2 expression with time to event variables (PFS, OS) it will be used 
a univariate Cox Regresion model. 
To evaluate the effect of BRCA1/2 expression with efficacy rate parameters it will be used chi-
square test if both of them are quantitative, and will be used an ANOVA analysis if one variable is 
quantitative and the other one are qualitative. 
To correlate BRCA1/2 expression with BRCA1/2 promoter methylation status:  
We will compare BRCA1/2 expression and BRCA1/2 promoter methylation status when they are 
binary data using chi-square test. 
If methylation status and expression data are given as continuous variables, they will be compared 
using statistical t (student-Fisher) or Wilcoxon test depending if it must be used a parametric or 
non-parametric test.  
If appropriate, additional analysis on all these biomarkers may be performed. 
 
9.2.4 
Other Analyses 
9.2.4.1 Biomarker Exploratory Analyses 
The biomarker analyses of the present study will be exploratory and primarily make use of 
descriptive statistical methods. For continuous variables, descriptive statistics including the mean, 
standard deviation, median, minimum and maximum values will be provided. Categorical variables 
will be summarized by numbers and proportions (if possible, the 95% confidence intervals will be 
calculated).  
Appropriate statistical methods will be used to investigate any possible relationship of biological 
subtypes/profiles and biomarker levels with the efficacy end-points and outcome, and to compare 
with data from healthy volunteers (if available). Any exploratory biomarker analyses, including 
additional sensitivity analyses, will be outlined in the specific statistical analysis plan/summary. 
9.2.5 
Other Subgroup Analyses  
Other exploratory subgroup analyses may be performed if deemed appropriate. 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 24 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
9.2.6 
Second Course Phase Analyses  
Exploratory second course phase analyses may be performed if deemed appropriate. 
 
 
 
 
10. 
TABLES Y FIGURES 
Table/Figure No. 
Title of Table/Figure 
 
1. 
BASELINE 
 
1.1. 
Study Information 
 
1.1.1. 
Study Information 
 
1.2. 
Disposition of Patients 
 
1.2.1 
Screen Failures 
 
1.2.2 
Number of Subjects Randomized by Site 
 
1.2.3 
Disposition of subjects 
 
1.2.4 
Analysis Sets 
 
1.3. 
Consort Study Flowchart 
 
Fig .1.3.1 
Consort Flowchart 
 
1.4. 
Baseline characteristics 
 
1.4.1 
Demographic Characteristics 
 
1.4.2 
Clinical-Pathological Characteristics 
 
1.4.3 
Local Laboratory Biomarkers 
 
1.4.4 
Baseline Lesions 
 
1.4.5 
Stratification Factors 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 25 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
1.5. 
Medical History 
 
1.5.1 
Medical History by Prefered Term 
 
1.5.2 
Most common (at least 5%) Medical and Surgical History by Preferred 
Term ITT Population 
 
1.6. 
Concomitant Treatments 
 
1.6.1 
Concomitant Medications by Standardized Medication Name Safety 
Population 
 
1.6.2 
Most common concomitant medications (at least 10% overall) by 
Standardized Medication Name Safety Population 
 
1.7. 
Previous Treatments 
 
1.7.1 
Prior Therapies for BC 
 
1.7.2 
Previous Treatment for Early BC.  
 
1.7.2 
Previous Treatment for MTX BC.  
 
 
 
1.8. 
Study Drug Exposure 
 
1.8.1 
Summary of Study Drug Exposure 
 
1.8.2 
Summary of Dose Modifications 
 
 
 
1.9. 
Subsequent Therapies 
 
1.9.1 
Subsequent Therapies for BC 
 
1.9.2 
Subsequent Chemotherapy for BC 
 
1.9.3 
Subsequent Hormone therapy for BC 
 
1.9.4 
Subsequent Targeted therapy for BC 
 
 
 
2. 
EFFICACY 
 
2.1. 
Overall Response Rate 
 
2.1.1 
Summary of Overall Response Rate Efficacy population 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 26 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
 
2.1.2 
Summary of Overall Response Rate ITT population 
 
 
 
2.2. 
Progression-free Survival 
 
2.2.1 
Progression-free Survival  Efficacy population 
 
Fig . 2.2.1 Progression-free Survival  Efficacy population 
 
2.2.2 
Progression-free Survival  ITT population 
 
Fig . 2.2.2 Progression-free Survival  ITT population 
 
 
 
2.3. 
Overall Survival 
 
2.3.1 
Overall Survival  Efficacy population 
 
Fig . 2.3.1 Overall Survival  Efficacy population 
 
2.3.2 
Overall Survival  ITT population 
 
Fig . 2.3.2 Overall Survival  ITT population 
 
 
 
3. 
SAFETY 
 
3.1. 
Treatment Emergent Adverse Event 
 
3.1.1 
Overview of Treatment-Emergent Adverse Events 
 
3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
3.1.3 
Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
3.1.4 
Grade 3 or Higher Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
3.1.5 
Grade 3 or Higher Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
3.1.6 
Most common (at least 10% in any treatment arm) Treatment-Emergent 
Adverse Events by Preferred Term 
 
3.1.7 
Serious Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term Safety Population 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 27 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
 
3.1.8 
Serious Drug-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term Safety Population 
 
3.1.9 
Treatment-Emergent Adverse Events by Grade 
 
3.1.10 
Drug-Related Treatment-Emergent Adverse Events by Grade 
 
3.1.11 
Serious Treatment-Emergent Adverse Events by Grade 
 
3.1.12 
Adverse Events from Laboratory according NCI CTC v4.03 by System 
Organ Class and Preferred Term 
 
 
 
3.1. 
Deaths 
 
3.2.1 
All-Cause Mortality Safety Population 
 
 
 
4 
OTHER ENDPOINTS 
 
 
4.1 
Changes of germline methylation pre and post treatment 
 
4.2 
Correlation between germline methylation status and efficacy outcome 
data 
 
4.3 
Correlation between germline methylation status and somatic methylation 
status 
 
4.4 
Correlation of methylation between primary and metastatic lesions 
 
4.5 
Correlation between expression data and promoter methylation status of 
BRCA1/2 and outcome data 
5 
EXPLORATORY OBJECTIVES (if performed) 
 
5.1 
Exploratory biomarkers of response or resistance to Olaparib 
 
5.2 
Review potential pharmacogenomics analyses related to drug response or 
adverse drug reactions 
 
5.3 
Specific mutations or epigenetic biomarkers identified in pre-therapy 
tumour specimens as potentially linked to treatment response 
The numbers of tables and figures do not have to match exactly with those of the statistical report. The 
feasibility and interest of performing some of the described tables and figures based on the available number of 
patients, data and biological samples. 
Please see Shells Tables, Listings and Figures.


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 28 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
11. 
APPENDIX (if applicable) 
See attachment “Shell TLFs GEICAM 2015-06 (COMETA-Breast Study).docx”  
 
12. 
BIBLIOGRAFHY /REFERENCES 
 
1. GEICAM, Protocol GEICAM/2015-06 Version 3.0 10 June 2019. 
2. ICH E9, Statistical Principles for Clinical Trials. 
3. ICH E3, Structure and Content of Clinical Study Reports. 
4. O’Shaughnessy J, Schwartzberg Lee, Danso MA, et al. Phase III Study of Iniparib Plus 
Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With 
Metastatic Triple-Negative Breast Cancer. J Clin Oncol 2014;32(34):3840-3847. 
5. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept 
trial. Lancet 2010 Jul 24;376(9737):235-44. 
 
13. 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Version No. 
Effective Date 
Modified 
section 
Description of changes 
1 
 
NA 
Creation of document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Statistical Analysis Plan - COMETA-Breast 
 
Version No.: 1                                                                                 Protocol No.: GEICAM/2015-06 
Version date: 22 September 2020                                                                            Page: 29 of 29 
 
Statistical Analysis Plan Template 
Version Nº 3/ Version date: Aug 22, 2018 
 
 
i O’Shaughnessy J, Schwartzberg Lee, Danso MA, et al. Phase III Study of Iniparib Plus 
Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic 
Triple-Negative Breast Cancer. J Clin Oncol 2014;32(34):3840-3847. 
ii Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. 
Lancet 2010 Jul 24;376(9737):235-44.