Measure of Outcomes in Patients With Advanced Ovarian Cancer According to Homologous Recombination Status and Matched Therapies in a Real-world Scenario: A Retrospective and Prospective, Multicenter, Two Cohorts Study
Conditions: Ovarian Cancer
Sponsor: Consorzio Oncotech

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 1 of 22 
 
 
The BeLIVE study 
Measure of outcomes in patients with advanced 
ovarian 
cancer 
according 
to 
Homologous 
Recombination status and matched therapies in a real-
world scenario.  
A retrospective and prospective, multicenter, two 
cohort study.   
 
 
 
Protocol Code: 
BeLIVE 
Protocol version: 
1.0 
Protocol date: 
08 February  2024 
Sponsor non-profit: 
Consorzio Oncotech per la ricerca clinica 
Principal Investigators: 
Michele Bartoletti, MD 
Mara Mantiero, MD 
Responsibles for Study 
Coordination: 
OncoTech, Consorzio per la ricerca, la formazione e le 
tecnologie avanzate in oncologia 
Statisticians                          Marcella Montico 
 
CONFIDENTIAL 
This document contains confidential information belonging to Sponsor. Except as may be otherwise agreed to in 
writing, by accepting or reviewing these materials, you agree to hold such information in confidence and not to 
disclose it to others (except where required by applicable law), nor to use it for unauthorized purposes. In the event 
of actual or suspected breach of this obligation Sponsor should be promptly notified. 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 3 of 22 
TABLE OF CONTENTS 
Protocol authorization ................................................................................................................................ 2 
Table of contents ........................................................................................................................................ 3 
Abbreviations ............................................................................................................................................... 5 
PROTOCOL SYNOPSIS ........................................................................................................................... 6 
Introduction .................................................................................................................................................. 9 
1. 
Background ............................................................................................................................................ 9 
1.1 
Bevacizumab ................................................................................................................................ 10 
1.2 
Homologous recombination deficiency (HRD) and synthetic lethality ........................ 10 
1.3 
PARP inhibitors ........................................................................................................................... 11 
1.4 
Open questions and aims of the current study .................................................................. 11 
2. 
Study design and methods .............................................................................................................. 12 
2.1 
Study design ................................................................................................................................ 12 
2.2 
Study population ........................................................................................................................ 12 
2.3 
Inclusion criteria ......................................................................................................................... 12 
2.4 
Exclusion criteria ........................................................................................................................ 13 
3. 
Objectives and endpoints................................................................................................................. 13 
3.1 
Primary objective ........................................................................................................................ 13 
3.2 
Secondary objectives ................................................................................................................ 14 
3.3 
Data collected .............................................................................................................................. 14 
4. 
Study duration and follow up .......................................................................................................... 15 
5. 
Number of centers .............................................................................................................................. 15 
6. 
Withdrawal criteria ............................................................................................................................. 15 
7. 
Statistical plan and data analysis ................................................................................................... 15 
7.1 
Sample size and power considerations ................................................................................ 15 
7.2 
Interim analysis ........................................................................................................................... 16 
7.3 
Analysis ......................................................................................................................................... 16 
8. 
Ethical and regulatory requirements ............................................................................................. 17 
8.1 
Informed consent ........................................................................................................................ 17 
9. 
Administrative aspect ........................................................................................................................ 18 
9.1 
Insurance ...................................................................................................................................... 18 
10. 
Data Collection Procedures ......................................................................................................... 18 
10.1 
Data Protection ............................................................................................................................ 18 
11. 
Publications of study protocol and results ............................................................................. 19 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 4 of 22 
12. 
Study contacts ................................................................................................................................ 19 
13. 
References ........................................................................................................................................ 21 
 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 5 of 22 
ABBREVIATIONS 
 
DFS 
Disease-Free Survival 
NGS 
Next Generation sequencing 
ORR  
Overall Response Rate 
OC 
Ovarian Cancer 
OS 
Overall Survival 
PARPi       Poli-ADP RIbose Polymerase inhibitors 
PFS 
Progression-Free Survival 
VUS 
Variants of uncertain significance  
 
 
 
 
 
 
 
 
 
 
 
 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 6 of 22 
PROTOCOL SYNOPSIS 
 
Study title 
BeLIVE 
Measure of outcomes in patients with advanced ovarian cancer 
according to Homologous Recombination status and matched 
therapies in a real-world scenario. A retrospective and prospective, 
multicenter, two cohorts study.   
 
Sponsor 
OncoTech, Consorzio per la ricerca, la formazione e le tecnologie 
avanzate in oncologia  
Principals 
Investigators 
Michele Bartoletti, MD 
Mara Mantiero, MD 
Steering commitee 
Michele Bartoletti, MD 
Mara Mantiero, MD 
Fabio Puglisi MD, PhD 
Francesco Raspagliesi, MD 
Consortium/network 
MITO Group, Others 
Study 
design 
and 
methods 
This is a retrospective and prospective, multicenter, observational, 
two-cohorts study aimed to evaluate clinical outcomes and safety 
of patients diagnosed with advanced high grade ovarian cancer 
whose tumor was tested for the homologous recombination (HR) 
status using a validated HR deficiency test between January 2021 
and January 2026.  
- 
Cohort A: Homologous Recombination Deficient (HRD) 
ovarian cancer patients treated with Olaparib plus Bevacizumab 
as maintenance therapies after partial or complete response to first 
line platinum-based chemotherapy.  
- 
Cohort B: Homologous Recombination Proficient (HRP) 
ovarian cancer patients treated as for standard clinical practice at 
clinician’s choice. 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 7 of 22 
Study population 
All patients diagnosed with advanced high grade ovarian cancer 
who have received a homologous recombination analysis using 
validated HRD test between January 2021 and January 2026 are 
eligible. Patients resulted HRD and treated with Olaparib plus 
Bevacizumab will be  included in Cohort A while patient with HRP 
tumors will be  included in the Cohort B. Patients enrolled in the 
“compassionate use” of Olaparib (CNN program) can be included 
as well as patients who have received therapies according to 
clinical practice.  
Inclusion criteria 
• 
Female, age ≥ 18 years at the time of diagnosis 
• 
Patients diagnosed with high-grade serous or endometroid 
ovarian, fallopian tube, or primary peritoneal cancer undergone to 
Homologous Recombination test with the MyChoice HRD assay, 
FoundationOne DX assay or another validated HRD test, between 
January 2021 and January 2026: 
o 
Patients with HRD score > 42 or Loss of Heterozygosity 
(LOH) score high or defined as HR deficient with other tests and 
treated with Bevacizumab and Olaparib after first line platinum-
based chemotherapy will be retrospectively or prospectively 
enrolled in Cohort A 
o 
Patients with HRD score < 42 or Loss of Heterozygosity 
(LOH) score low or defined as HR proficient with other tests and 
treated with first line platinum-based chemotherapy with or without 
bevacizumab or others targeted agents will be retrospectively or 
prospectively enrolled in Cohort B 
• 
Patients must be able to understand the study procedures 
and agree to participate in the study by providing written informed 
consent. 
Exclusion criteria 
• 
Patients who have not performed a validated Homologous 
Recombination test on tumor sample.  
• 
Patients with germline or somatic BRCA 1 or 2 mutations  
• 
Patients death at the time of inclusion in the current study 
 
Primary objective 
• 
Evaluate the clinical outcomes as measured by progression-
free survival (PSF) and overall survival (OS) in patients in each 
study Cohorts.  
• 
Evaluate the safety of targeted agents (olaparib, niraparib,  
bevacizumab) used alone or in combination measured by 
incidence of adverse events according to the CTCAE, 
discontinuation rate from therapies and relative/absolute dose 
intensity in each study Cohorts.  

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 8 of 22 
 
Secondary objectives • 
To describe the clinical outcomes according to disease 
stage, surgical timing, residual disease after surgery in each cohort 
• 
To describe the clinical characteristics of patients for which 
the combination therapy was offered (Cohort A); 
• 
To describe the treatment approach to HRP patients in a real 
word scenario in Italy (Cohort B).  
 
Duration of 
participation 
Patients with available HRD test result at the time of study entry 
will be retrospectively or prospectively enrolled. Patients will be 
followed up prospectively up to 3 years from enrollment for primary 
and secondary objectives. 
 
Approximate Number 
of Patients 
Give the retrospective and prospective nature of the trial, no pre-
specified sample size has been planned. The estimated sample 
size is about 300 patients.  
 
Number of Study 
Centers 
 21 centers will be involved in the study 
Withdrawal criteria 
During the study a patient must be discontinued if any of the 
following apply:  
• 
Consent withdrawal at the patient’s own request or at the 
request of their legally authorized representative;  
• 
Termination of the study. 
 
 
 
 
 
 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 9 of 22 
INTRODUCTION  
 
Ovarian cancer is the second most frequent gynecological tumor but is the first in order of 
mortality1. Its relative low incidence and the absence of screening programs, represent major 
limitations to early disease detection2. The high mortality rate depends also on the lack of 
early symptoms, which means that most patients are diagnosed at advanced stage of 
disease, and on the limited results obtained from treatments. In fact, although ovarian cancer 
is considered a chemo-sensitive cancer, long-term control of the tumor is un unmet need 
since nearly 70% of patients will develop resistance to cytotoxic agents, in particular to 
platinum salts3. The median progression-free survival (PFS) for patients with advanced 
disease ranges between 16 and 23 months while the median overall survival (OS) lies 
between 31 and 65 months and strategy to improve outcome are urgently needed.  
1. 
Background 
For patients with ovarian cancer, cytoreductive surgery, aimed to remove all the 
macroscopic implants from the abdomen and the pelvis, represents the only curative 
treatment option and is the therapeutic mainstay in early and advanced disease. Platinum 
salts, instead, used in combination with taxanes, are the standard first line chemotherapeutic 
agents employed. However, even when an optimal cytoreductive surgery is performed and 
6 to 8 cycles of a platinum-based chemotherapy are administered, prognosis for patients 
with advanced ovarian cancer remains poor, with approximately 70–80% of patients 
experiencing a disease recurrence within 3 years. Consequently, the 5-year survival rate is 
still below 50%. 
Thus, it is necessary to develop additional therapeutic strategy, that can prolong the benefit 
of platinum-based chemotherapy, in order to avoid recurrence and to improve overall 
survival. Improving the effectiveness of systemic treatment has been the major challenge of 
gynecologic oncology research. In the past 30 years most of changes have included using 
different treatments schedule (e.g. dose dense regimens), different modalities of treatment’ 
administration (e.g. intraperitoneal chemotherapy and HIPEC) and different platinum-based 
combinations. (e.g. pegylated liposomal doxorubicin along with platinum salts). The first 
targeted agent approved by the Food and Drugs Administration (FDA) for the treatment of 
advanced OC was the humanized anti- VEGF antibody bevacizumab, back in 20174. A 
further turning point in the first line setting was the publication of results from the biomarker-
driven phase 3, SOLO1 study, following which, olaparib maintenance was established as 
the new standard of care in advanced ovarian cancer patients harboring a BRCA 1 or 2 
deleterious mutation5. Moreover, the SOLO1 trial paved the way for two other milestone 
trials, the PRIMA and PAOLA1 studies, whose results have broadened the spectrum of 
patients who can benefit from a PARPi maintenance also to those with tumors presents 
Homologous Recombination deficiency (HRD)6,7. Although these results are encouraging 
and will probably modify the ovarian cancer’s course, especially in the disease presenting a 
BRCA 1-2 mutation, the occurrence of PARPi resistance, which seems to overlap partially 
with platinum-resistance, is becoming an unmet clinical need and a major challenge for the 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 10 of 22 
near future8. Moreover, not all ovarian cancers will benefit from treatment with PARPi and, 
non-serous OC patients are poorly represented in pivotal clinical trials and thus have limited 
therapeutic options both in the up-front setting or in case of disease recurrence. In the latter 
case, systemic chemotherapy has been historically guided by the time span from the last 
platinum therapy and disease recurrence, the so-called platinum-free interval. In this setting, 
targeted agents include bevacizumab for platinum resistant or sensitive disease and PARPi 
as maintenance or active therapy, even if the current early use of these agents, alone or in 
combination, limits their availability for recurrent ovarian cancer. 
1.1 
Bevacizumab 
Bevacizumab is a recombinant, humanized anti-VEGF monoclonal IgG1; its mechanism of 
action is represented by selective binding to circulating VEGF; in this way, Bevacizumab 
can block the biologic activity of human VEGF, provoking a reduction in the vascularization 
of tumors, thereby inhibiting tumor growth9. 
In the GOG-0218 study, a double-blind, placebo-controlled, phase 3 trial, women diagnosed 
with stage III or stage IV epithelial ovarian cancer, who had previously undergone debulking 
surgery, were randomly assigned to receive one of the three following treatments: 
chemotherapy with carboplatin plus paclitaxel versus chemotherapy with carboplatin plus 
paclitaxel in association with bevacizumab versus chemotherapy with carboplatin plus 
paclitaxel in association with bevacizumab, followed by bevacizumab as maintenance 
monotherapy. The results of this study have shown that the use of bevacizumab, during and 
up to 10 months after carboplatin and paclitaxel chemotherapy, prolonged the median 
PFS10. 
In the ICON7 study, a randomized, phase III trial, that has involved 1528 patients with high-
risk early-stage disease or advanced stage ovarian carcinoma, women were randomized to 
receive conventional carboplatin plus paclitaxel for 6 cycles in the first arm, or the same 
treatment plus bevacizumab during chemotherapy, with bevacizumab monotherapy 
continuing for an additional 36 weeks in the second arm. The results of this trial have shown 
an improvement of PFS and of OS in the second arm. Moreover, women who had the bigger 
benefit from adding bevacizumab to chemotherapy, were those with the higher risk of 
recurrence11. 
As a result of these evidence, the addition of the antiangiogenic agent bevacizumab to 
carboplatin plus paclitaxel, followed by bevacizumab alone, is actually a standard option in 
patients with newly diagnosed advanced ovarian cancer12. 
1.2 
 Homologous recombination deficiency (HRD) and synthetic lethality  
Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair 
pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA 
repair-defective tumors, in particular homologous recombination (HR), are highly sensitive 
to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the 
synthetic lethality approach, which may lead to new therapeutic strategies. It is well known 
that poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors show the 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 11 of 22 
synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins 
that are required for efficient HR13.  
1.3 
 PARP inhibitors 
Recently, in the SOLO1 trial, the PARP inhibitor Olaparib provided a substantial PFS benefit 
as maintenance monotherapy in patients with newly diagnosed advanced ovarian cancer, 
whose tumors had a BRCA1 o BRCA2 mutation and who had a complete or partial clinical 
response after platinum-based chemotherapy 5. However, HRD is not limited to tumors with 
BRCA mutations and is present in approximately 50% of high-grade serous ovarian tumors. 
Moreover, the addition of an antiangiogenic agent to a PARP inhibitor in phase 2 studies 
involving patients with relapsed platinum-sensitive ovarian cancer resulted in longer 
progression-free survival than the use of a PARP inhibitor alone. 
PAOLA 1 is a randomized, double-blind phase 3 trial, in which eligible patients with newly 
diagnosed, advanced, high-grade ovarian cancer, who had a complete or partial response 
after first-line platinum-taxane chemotherapy plus bevacizumab, were randomized to 
receive olaparib or placebo in association with bevacizumab in maintenance therapy up to 
24 months, regardless the BRCA mutation status. After a median follow-up of 22.9 months, 
the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 
16.6 months with placebo plus bevacizumab. The hazard ratio (olaparib group vs. placebo 
group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with 
tumors positive for homologous-recombination deficiency (HRD), including tumors that had 
BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), 0.43 (95% CI, 
0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations 
(median progression-free survival, 28.1 vs. 16.6 months) and 0.92 (median PFS 16.9 vs 
16.0 months) in HRD negative patients suggesting no additional benefit of olaparib in the 
last group12. 
In the same setting, PRIMA trial, is a randomized, double-blind, phase 3 trial in which 
patients with newly diagnosed, advanced, high grade serous and endometrioid ovarian 
cancer responding to first line platinum-paclitaxel chemotherapy were randomized to receive 
niraparib, which is another PARP inhibitor, or placebo, as maintenance treatment. Of the 
733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-
recombination deficiency. Among the patients in this category, the median progression-free 
survival was significantly longer in the niraparib group than in the placebo group6.  
1.4 
 Open questions and aims of the current study 
According to results presented above, is possible to conclude that the magnitude of benefit 
from targeted therapies in newly diagnosed ovarian cancer is deeply affected by the 
biomarkers’ status (BRCA and HR status). While it appears clear that BRCA mutated 
patients benefit the most from PARPi and the addition of bevacizumab seems not providing 
further advantages, the best strategy for HRD and HRP patients is far from be defined. For 
HRP patients, current strategies include the incorporation of bevacizumab with 
chemotherapy and then as maintenance or the use of niraparib as maintenance after 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 12 of 22 
chemotherapy in case of partial of complete response. Despite this, the best approach is 
debated, and chemotherapy alone is also a reasonable option for these patients. Moreover, 
for HRD patients, the use of olaparib plus bevacizumab raises concerns about toxicities 
since 20% of patients in the PAOLA 1 trial discontinued treatments for adverse events. 
Starting from this scenario, the aims of the current study are to describe the clinical 
outcomes and safety of patients with advanced ovarian cancer receiving targeted therapies 
according to tumor biomarker’s status in a real word setting. Secondary objective is to 
describe the approach to HRP patients in real practice in Italy.  
2. 
Study design and methods 
2.1 
Study design 
This is a retrospective and prospective, multicenter, observational, two-cohorts study aimed 
to evaluate clinical outcomes and safety of patients diagnosed with advanced high grade 
ovarian cancer whose tumor was tested for the homologous recombination status using a 
validated HRD test between January 2021 and January 2026:  
- 
Cohort A: Homologous Recombination Deficient (HRD) ovarian cancer patients treated 
with Olaparib plus Bevacizumab as maintenance therapies after partial or complete 
response to first line platinum-based chemotherapy.  
- 
Cohort B: Homologous Recombination Proficient (HRP) ovarian cancer patients 
treated as for standard clinical practice at clinician’s choice. 
Alive patients who have finished the first line treatment (including maintenance) with or 
without disease progression while signing the informed consent form will be enrolled 
retrospectively. 
Alive patients candidate to receive a first line therapy will be enrolled prospectively as soon 
as molecular data (BRCA status and HRD) are available.  
 
2.2 
 Study population 
All patients diagnosed with advanced high grade ovarian cancer who have received an 
homologous recombination analysis using a validated HRD test, between January 2021 and 
January 2026, are eligible. Patients resulted HRD and treated with Olaparib plus 
Bevacizumab will be retrospectively or prospectively included in Cohort A, while patient with 
HRP tumors will be retrospectively or prospectively included in the Cohort B. Patients 
enrolled in the “compassionate use” of Olaparib (CNN program) can be included as well as 
patients who have received therapies according to clinical practice.  
2.3 
 Inclusion criteria 
• Female, age ≥ 18 years at the time of diagnosis  
• Patients diagnosed with high-grade serous or endometroid ovarian, fallopian tube, 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 13 of 22 
or primary peritoneal cancer undergone to Homologous Recombination test 
between January 2021 and January 2026: 
o Patients with HRD score > 42 or Loss of Heterozygosity (LOH) score high or 
defined as HR deficient with other tests and treated with Bevacizumab and 
Olaparib after first line platinum-based chemotherapy will be retrospectively or 
prospectively enrolled in Cohort A 
o Patients with HRD score < 42 or Loss of Heterozygosity (LOH) score low or 
defined as HR proficient with other tests and treated with first line platinum-
based chemotherapy with or without bevacizumab or others targeted agents 
will be retrospectively or prospectively enrolled in Cohort B 
• Patients must be able to understand the study procedures and agree to participate 
in the study by providing written informed consent (see details in informed consent 
section). 
 
2.4 
 Exclusion criteria 
• Patients who have not performed a validated Homologous Recombination tests 
are not eligible for this study.  
• Patients with germline or somatic BRCA 1 or 2 mutations  
• Patients death at the time of inclusion in the current study 
3. 
Objectives and endpoints 
3.1 
 Primary objective 
The primary objective of the study is to evaluate the clinical outcomes and the safety in 
patients treated with targeted anticancer therapies in each study cohort.  
The clinical outcomes that will be measured in both study cohorts are:  
o progression-free survival (PSF) as the time from treatment’s start to disease 
progression or death for any cause 
o overall survival (OS) as the time from treatment’s start to death for any cause 
Relatively to safety, in detail the following parameters will be recorded:  
o Toxicity evaluated according to CTCAE vers 5.0 
o Percentage of patients with dose reductions 
o Percentage of patients with dose interruptions due to toxicity 
o Percentage of patients with treatment discontinuations due to toxicity 
o Toxicity according to initial dose of targeted agents 
o Incidence of myelodysplastic syndrome and acute myeloid leukaemia in patients 
receiving PARPi 
 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 14 of 22 
3.2 
 Secondary objectives 
The secondary objectives are to collect the clinical outcomes, according to disease stage, 
surgical timing, residual disease after surgery in each cohort; therefore, to describe the 
clinical characteristics of patients for which the combination therapy was offered (Cohort 
A) and to describe the treatment approach to HRP patients in a real word scenario in Italy 
(Cohort B).  
 
3.3 
 Data collected 
Baseline data: Patient demographics and disease/treatment history will be collected from 
clinical records 
 
1) 
Demographic: age, weight, height, pre-existing hypertension and comorbidities, 
and ECOG at time of enrollment 
2) 
Medical/family history of cancer: history of other cancers, family history of cancers 
3) 
Ovarian cancer diagnosis history: age of patient at cancer diagnosis, tumor 
histology, FIGO stage, primary tumor location, CT Scan (Thoracic, Abdominal, 
Pelvic) 
4) 
Biomarker data collected per clinical routine and reported as available from medical 
charts: BRCA/HRD status. Type of HRD test performed; 
5) 
Ovarian cancer treatment history: 
• 
Time of debulking surgery (primary or interval) 
• 
Outcome post debulking surgery (primary or interval): Visible Residual 
Disease or No visible residual disease  
• 
Description of prior chemo/platinum lines (including drugs/regimens, start 
and end dates, and frequency) 
• 
Response to last chemo/platinum line 
• 
Weeks after last platinum administration 
6) 
In case of disease relapse/progression, date of disease relapse or progression, site 
of relapse/progression, CA125 at disease relapse/progression; 
7) 
Date of second surgery if performed; 
8) 
Description of second line chemotherapy (including drugs/regimens, start and end 
dates, and frequency) and its outcome in term of recist or CGIG criteria f tumor 
response (CA125 based); 
9) 
Status (death or alive) and respective date.  
 
Patient’s characteristics and disease profile: 
10) Platelet, neutrophiles and hemoglobin count at targeted treatment initiation 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 15 of 22 
11) CA125 levels as collected per standard of care at the time of treatment’s start and 
at the time of recurrence 
12) Starting PARPi dose 
13) Time and reason for dose reduction(s), including new dose prescribed 
14) Time and reason for treatment termination 
15) Duration of treatment 
16) Post targeted therapy progression treatments: type and outcome of subsequent 
chemotherapy lines 
 
4. 
Study duration and follow up 
Patients with available HRD test result at the time of study entry will be retrospectively or 
prospectively enrolled. Patients will be retrospectively or prospectively enrolled from 
January 2021 to January 2026. The study will close in January 2029, this means that the 
last patients enrolled will be followed up prospectively for up to 3 years for primary and 
secondary objectives, independently of whether they are taking therapies or not.  
5. 
Number of centers 
This multicenter observational study involves approximately 21 Italian sites. 
 
6. 
Withdrawal criteria 
Specific reasons for discontinuing from the current study include the following reasons:  
o Withdrawal of consent;  
o Termination of the study. 
 
7. 
Statistical plan and data analysis 
 
7.1 
Sample size and power considerations 
Given the retrospective and prospective nature of the trial, the sample size is estimated 
according to the number of patients available. 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 16 of 22 
At least 300 patients are to be selected considering both cohorts together. As HRD patients 
are about 50% of ovarian cancer patients, the two cohorts will consist of approximately 150 
patients each.  
With this number it is judged that the progression-free survival after first line treatments 
(independently from targeted agents used) will be estimated with sufficient accuracy.  
With the available sample size, the width of 95% confidence intervals for frequency of toxicity 
in the two cohorts will be as follows: 
N 
Observed 
Frequency Width of 95% CI Lower Limit Upper limit 
150 10% 
10% 
5% 
15% 
150 20% 
13% 
14% 
26% 
150 30% 
15% 
23% 
37% 
150 40% 
16% 
32% 
48% 
150 50% 
16% 
42% 
58% 
 
7.2 
Interim analysis 
An interim analysis after 50% (i.e. about 150 patients) of the recruitment will be performed 
in order to obtain a first insight of the results 
7.3 
Analysis  
PFS will be measured from the date of treatment’s start to the date of first observed disease 
progression (relapse) or death. Standard statistics will be used to evaluate data (Kaplan 
Mayer; median and 95 % CI). In order to estimate the impact of therapy among our cohort 
of patients, all covariates (main prognostic factor for advanced ovarian cancer as residual 
disease, stage, Histotype) will be entered in a univariate and multivariate model (if the 
number of events will suffice) in order to identify predictors of survival outcomes. Survival 
outcomes will be assessed using Cox proportional hazard model. 95% confidence intervals 
(95%CI) will be estimated for each comparison when appropriate.  
Other analysis will include summary statistics, including number and percentage for 
categorical variables and number of patients, mean, standard deviation, median, minimum, 
and maximum for continuous variables. 95% CI will be estimated when appropriate.   
Adverse event intensity/severity will be coded using the current version of CTCAE and will 
be summarized for all treated participants. Incidence of AEs occurring during the study will 
be summarized by system organ class and preferred term. Adverse events will also be 
summarized by causality and grade. Serious adverse events will be listed separately. 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 17 of 22 
8. 
 Ethical and regulatory requirements 
The procedures set out in this study protocol are designed to ensure that the promoter and 
the Investigators abide by the principles of the Good Clinical Practice guidelines of the 
International Conference on Harmonization (ICH) and the Declaration of Helsinki in the 
conduct, evaluation and documentation of this study. The study will be carried out adhering 
to local legal requirements and the applicable national law, whichever represents the greater 
protection for the individual.  
8.1 
Informed consent 
Informed consent will be collected during routine visits. The process of obtaining informed 
consent should be documented in the patient source documents. The date when a subject’s 
Informed Consent was actually obtained will be captured in database form. 
The Local Principal Investigator or his/her representative will explain the nature of the study 
to participant and answer all questions regarding the study and will:   
• 
Ensure that each subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study 
• 
Inform each patients that their participation is voluntary and that may 
withdraw their consent at any time and for any reason.  
• 
Ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided 
• 
Ensure that the original, signed Informed Consent Forms are stored in 
the Investigator’s Study File 
• 
Ensure that a copy of the signed Informed Consent Forms is given to the 
subject 
It is understood that the subjects will be considered unavailable only after having made all 
reasonable efforts to contact them, such as by: 
• checking whether they are still alive; 
• browsing through their clinical records; 
• contacting such telephone numbers as may be available; 
• obtaining contact information from population and/or health care registers. 
 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 18 of 22 
9. 
Administrative aspect 
This study is a non-profit investigator-initiated trial. The promoter OncoTech, Consorzio per 
la ricerca, la formazione e le tecnologie avanzate in oncologia. An agreement between the 
Promoter and each participating centre will be stipulated.  
Study protocol, patient information and informed consent will be submitted to the appropriate 
Ethical Committees for approval. At each centre, the study will only be started after being 
approved by the institutional Ethical Committee. The promoter will inform the Ethical 
Committees about any changes in the study protocol which could interfere with the patient’s 
safety. Furthermore, the institutional review board will be informed of the planned or 
premature end of the study.  
9.1 
 Insurance 
Being an observational study, and according to Italian guidelines for observational studies 
(31/03/2008 in G.U. n. 76), no additional insurance policy will be needed beyond those 
already required by current medical practice. 
10. 
Data Collection Procedures 
Patient registration and data collection are electronically managed through an Electronic 
Data Capture system.   
The Sponsor will supply the above-mentioned electronic Case Report Forms (eCRFs) to 
participating centers.  
All eCRFs are to be completed and reviewed by the Investigator/designated Staff. 
It is each Investigator’s responsibility to ensure that eCRFs accurately reflect data contained 
in subject’s records (e.g., source documents). The Investigator is also responsible for 
assuring that data entry and updates are performed in a timely manner. 
Automatic validation programs check for data discrepancies in the eCRFs allow modification 
or verification of the entered data by the investigator staff. 
Contacts for registration will be supplied in the section 12. 
10.1 Data Protection 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the clinical outcomes and the safety 
in patients treated with targeted anticancer therapies in each study cohort. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and regulations. 
The Investigator/Sponsor ensures that the personal data will be: 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 19 of 22 
• processed fairly and lawfully 
• collected for specified, explicit, and legitimate purposes and not further processed in 
a way incompatible with these purposes 
• adequate, relevant, and not excessive in relation to said purposes 
• accurate and, where necessary, kept current 
Explicit consent for the processing of personal data will be obtained from the participating 
subject (or his/her legally acceptable representative) before collection of data. Such consent 
should also address the transfer of the data to other entities and to other countries. 
The subject has the right to request through the Investigator access to her personal data 
and the right to request rectification of any data that are not correct or complete. Reasonable 
steps should be taken to respond to such a request, taking into consideration the nature of 
the request, the conditions of the study, and the applicable laws and regulations. 
 
11. 
Publications of study protocol and results 
The information regarding the study and all results, data, information developed, generated 
or derived from the same study are confidential and exclusive property of the promoting site. 
The final publication of trial results will be written on the basis of the analysis performed as 
approved by the steering committee. Publications will be decided by the Principal 
Investigator in agreement with the steering committee. 
12. 
Study contacts 
Principal Investigator: Michele Bartoletti, MD Centro di Riferimento Oncologico di Aviano 
IRCCS. Michele.bartoletti@cro.it 
 
 
Co-Investigator: Mara Mantiero, MD, Istituto Nazionale Tumore (INT), Milano 
Mara.Mantiero@istitutotumori.mi.i 
 
Coordinating center: Centro di Riferimento Oncologico di Aviano IRCCS, via Franco Gallini 
2, Aviano (PN), Italy 
 
 
Study Statisticians: Marcella Montico, Centro di Riferimento Oncologico di Aviano IRCCS 
 
 
Contacts for registration and enrollment: 
Centro di Riferimento Oncologico di Aviano 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 20 of 22 
Via F. Gallini 2, 33081 Aviano (Italy) 
Silvia Flora, sflora@cro.it 
Riccardo Spizzo, rspizzo@cro.it 
Michele Bartoletti, michele.bartoletti@cro.it 
 
 
Contacts for regulatory issues: 
Clinical Research Technology 
Via S. Leonardo Trav. Migliaro, 84131 Salerno  (Italy) 
+39 081 19572570 | Fax +39 089 7724155 | belive@cr-technology.com 
 
 
 
 
 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
Page 21 of 22 
13. 
References 
1- Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer 
Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 
Cancers in 185 Countries. CA Can J Clin 2018;68(6):394–424. 
 
2- Menon U, Gentry-Maharaj A, Burnell M, Singh N, Ryan A, Karpinskyj C, et al. Ovarian 
Cancer Population Screening and Mortality after Long-Term Follow-up in the UK 
Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A Randomised Controlled 
Trial. Lancet 2021;397(10290):2182–93. 
 
3- Lee J-Y, Kim S, Kim YT, Lim MC, Lee B, Jung K-W, et al. Changes in ovarian cancer 
survival during the 20 years before the era of targeted therapy. BMC Cancer 2018; 
18:601. 
 
4- Research, C. for D.E. and FDA Approves Bevacizumab in Combination with 
Chemotherapy for Ovarian Cancer. FDA, 2019. 
 
5- Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, et al. 
Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. 
Engl. J. Med. 2018;379:2495–505. 
 
6- Gonzalez-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza 
MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. 
J. Med. 2019;381:2391–402. 
 
7-Ray-Coquard Isabelle, Pautier Patricia, Pignata Sandro, P´erol David, Gonz´alez- 
Martín Antonio, Berger Regina, et al. Olaparib plus bevacizumab as first-line 
maintenance in ovarian cancer. N Engl J Med 2019;381(25):2416–28. 
 
8-Bartoletti M, Cecere SC, Musacchio L, Sorio R, Puglisi F, Pignata S. Recurrent ovarian 
cancer in the era of poly-ADP ribose polymerase inhibitors: time to reassess established 
clinical practices. ESMO Open 2021;6(3):100135. 
 
9-Kotowski, K., Przystupski, D., Kwiatkowski, S., Kolasińska, K., Bartosik, W., Górska, 
A., … Kulbacka, J. (2018). Contemporary management and novel therapies in ovarian 
cancer – literature review. World Scientific News, (111), 51–63. 
 
10-Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the 
primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473-83. 
 
11-Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian 
cancer. N Engl J Med 2011; 365: 2484-96. 
 

Measure of outcomes in patients with advanced ovarian cancer according to 
Homologous Recombination status and matched therapies in a real-world 
scenario.  
A retrospective and prospective, multicenter, two cohort study (The BeLIVE trial). 
BeLIVE trial  
Protocol version 1.0 - 
08/Feb/2024 
 
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12-Ray-Coquard, I. et al. (2019) ‘Olaparib plus bevacizumab as first-line maintenance in 
ovarian cancer’, New England Journal of Medicine, 381(25), pp. 2416–2428. doi: 
10.1056/NEJMoa1911361. 
 
13-Jiang, X.; Li, X.; Li, W.; Bai, H.; Zhang, Z. PARP inhibitors in ovarian cancer: 
Sensitivity prediction and resistance mechanisms. J. Cell. Mol. Med. 2019, 23, 2303–
2313