Clinical trial NCT03767335
Conditions: Advanced or Metastatic Breast Cancer
Keywords: Advanced Breast Cancer Metastatic Breast Cancer PI3K inhibitor HER2-positive
Sponsor: Menarini Group
Start date: 2018-11-13; Completion date: 2024-02-23
Enrollment: 62 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this open-label, dose-escalation, phase Ib study is to identify the appropriate dose of MEN1611 to be used in combination with Trastuzumab with/without Fulvestrant for the treatment of advanced or metastatic HER2-positive breast cancer

Detailed description:
This Phase Ib study will investigate the safety and anti-tumor activity of daily oral doses MEN1611 in combination with Trastuzumab with/without Fulvestrant in female and male patients affected by advanced or metastatic HER2-positive breast cancer. Fulvestrant will be added to the post-menopausal patients with hormone-sensitive disease.

MEN1611 is an investigational drug which blocks a protein called PI3K (phosphoinositide 3-kinase) involved in cancer cells growth. The Maximum Tolerated Dose (MTD) of MEN1611 given as single agent was assessed in a phase I trial in patients with advanced solid tumors.

This Phase IB will start with a dose escalation part (Step 1) to identify the MTD of MEN1611 given in combination with Trastuzumab with/without Fulvestrant.

The study will continue with a cohort expansion (Step 2) to investigate the anti-tumor activity of the selected MEN1611 dose level considered to be tolerable by a Safety Review Committee.

Arms: arm 1: MEN1611 + Trastuzumab +/- Fulvestrant
Interventions: intervention 1: MEN1611 intervention 2: Trastuzumab intervention 3: Fulvestrant
Intervention descriptions: intervention 1: MEN1611 oral dose administered twice daily for a continuous 28-day cycle intervention 2: Trastuzumab solution for infusion administered weekly via IV intervention 3: Fulvestrant solution for injection administered monthly via IM (only for HR-positive postmenopausal women)

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
FINAL VERSION 5.0, 3 MARCH 2022 
OPEN-LABEL, MULTICENTRE, PHASE IB DOSE-ESCALATION 
STUDY OF MEN1611, A PI3K INHIBITOR COMBINED WITH 
TRASTUZUMAB ± FULVESTRANT, IN SUBJECTS WITH 
PIK3CA MUTATED HER2-POSITIVE LOCALLY RECURRENT 
UNRESECTABLE (ADVANCED) OR METASTATIC (A/M) 
BREAST CANCER PROGRESSED TO ANTI-HER2 BASED 
THERAPY 
Study Code: 
MEN1611-01 
Study Nick Name/Acronym: 
B-PRECISE-01
EudraCT Number: 
2017-004631-36
Investigational Medicinal Product: MEN1611 oral capsules 
Development phase of the Study: 
Phase Ib 
SPONSOR 
CO-ORDINATING INVESTIGATOR 
CONTRACT RESEARCH 
ORGANISATION 
Menarini Ricerche S.p.A. 
Clinical Sciences 
Via Sette Santi, 1 
50131 Florence, Italy 
Phone: +39 05556809990 
Fax:+390555680597 
 
Institute Jules Bordet 
Boulevard de Waterloo 125 
B-1000 Brussels, Belgium
E-mail:
Phone: 
Fax: 
IQVIATM 
500 Brook Drive, Green Park, 
Reading, 
RG2 6UU (United Kingdom) 
STATEMENT OF CONFIDENTIALITY 
The information in this document contains trade secrets and proprietary commercial information of Menarini Group 
that is privileged or confidential and may not be disclosed unless such disclosure is required by law. In any case, persons 
to whom the information is disclosed must be informed that the information is privileged or confidential and may not 
be further disclosed without written authorisation by Menarini Group. 
NCT #: NCT03767335


Clinical Study Protocol 
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1. SIGNATURES 
The Signatories have read the clinical study protocol (Version 5.0, dated 03 March 2022) titled 
“Open-label, multicentre, Phase Ib dose-escalation study of MEN1611, a PI3K inhibitor combined 
with trastuzumab ± fulvestrant, in subjects with PIK3CA mutated HER2-positive locally recurrent 
unresectable (advanced) or metastatic (a/m) breast cancer progressed to anti-HER2 based therapy” 
carefully and agree to adhere to its provisions. Changes to the protocol have to be stated by the 
Sponsor in amendments to the clinical study protocol which, if are substantial, have to be authorised 
by the Competent Authorities and Ethics Committees before translating them into action. 
 
Signature 
Date 
 
Sponsor’s Representative 
 
Menarini Ricerche S.p.A. 
 
.......... 
 
 
.............................. 
 
Signature 
Date 
 
Co-ordinating Investigator 
 
Institute Jules Bordet – Brussels 
.......... 
 
 
.............................. 
8th March 2022
March 10th 2022


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PRINCIPAL INVESTIGATOR’S STATEMENT 
Clinical Statement 
My signature below documents my agreement with the contents of this clinical study protocol 
(Version 5.0, dated 03 March 2022) titled “Open-label, multicentre, Phase Ib dose-escalation study 
of MEN1611, a PI3K inhibitor combined with trastuzumab ± fulvestrant, in subjects with PIK3CA 
mutated HER2-positive locally recurrent unresectable (advanced) or metastatic (a/m) breast 
cancer progressed to anti-HER2 based therapy” with regard to the execution of the study and the 
required documentation/data collection. I agree to comply with this clinical study protocol in its 
entirety and with the International Council for Harmonisation (ICH) guidelines for Good Clinical 
Practice (GCP). 
Anti-Corruption Statement 
I and my collaborators agree to perform any activity in accordance with the principles, any 
international anti-corruption legislations, such as the Organisation for Economic Co-operation and 
Development Convention on Combating Bribery of Foreign Public Officials in International Business 
Transactions, United Kingdom Bribery Act and United States Foreign Corrupt Practices Act, 
including Italian Legislative Decree 231/2001. In particular, during the performance of the study, I 
will not, or not cause any of my collaborators to directly or indirectly offer, pay, give, or promise to 
pay or give or receive any payment or gift of any money or thing of value to or from any government 
officer to influence any acts or decisions or to induce such officer to use its influence to effect or 
influence the decision of the relevant government body or any other decision maker. I accept to 
promptly inform the Sponsor in writing in case of violations of or deviations from any of the above 
prescriptions in the conduct of the study and I acknowledge and accept Sponsor’s rights to conduct 
audits in order to verify compliance with the above during or in connection with the performance of 
the study. I agree and accept that a violation of any of the above prescriptions may result in the 
termination of the research activities of the site I work in and/or the entire study. 
Principal Investigator  
Signature 
Date 
............................................................. ............................................................. .............................. 


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2. PROTOCOL SYNOPSIS 
Clinical Study Protocol 
Number  
MEN1611-01 
Title 
Open-label, Multicentre, Phase Ib Dose-escalation Study of 
MEN1611, a PI3K Inhibitor Combined with Trastuzumab ± 
Fulvestrant, in Subjects with PIK3CA Mutated HER2-positive 
Locally Recurrent Unresectable (advanced) or Metastatic (a/m) 
Breast Cancer Progressed to Anti-HER2 Based Therapy. 
Acronym 
B-PRECISE-01 
Phase 
Ib 
Indication 
Phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene 
(PIK3CA) mutated human epidermal growth factor receptor-2 
(HER2)-positive, locally recurrent, unresectable advanced or 
metastatic (a/m) breast cancer, in subjects pre-treated with at least 
2 lines of anti-HER2 based therapy. 
Number of sites and 
countries 
Approximately 50 European, Russian and US sites. 
Investigational Medicinal 
Product, Treatment regimen 
(including route of 
administration) 
MEN1611, oral capsule: 16 mg capsules to be administered twice 
daily (BID) at three ascending dose cohorts: 16 mg, 32 mg and 
48 mg BID for a total daily dose of 32 mg, 64 mg and 96 mg, 
respectively. 
 
 
 
 
Trastuzumab, solution for infusion: 6 mg/kg (over 30 minutes) to 
be administered every 3-weeks for new patients to be included in 
the study at the time of this Protocol version 4.0 is in force (patients 
on 3-weekly trastuzumab administration schedule); 2 mg/kg (over 
30 minutes) to be administered weekly for patients already included 
in the study at that time and continuing the weekly trastuzumab 


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administration schedule). Premedication may be given according to 
local practice. 
Note: a loading IV dose could be administered if considered 
appropriate by the investigator based on the time elapsed from the 
last trastuzumab dose prior to study enrolment (see section 8.4.2 for 
details).  
Fulvestrant, solution for injection: Intramuscular (IM) 500 mg to be 
administered 
only 
to 
hormone 
receptor 
(HR)-positive 
postmenopausal subjects every 4 weeks from Day 1 of Cycle 1. An 
additional dose of fulvestrant 500 mg has to be administered on 
Day 15 of Cycle 1 to those subjects who were not under fulvestrant 
treatment prior Cycle 1 Day 1. 
MEN1611 will be given in combination with IV infusion of 
trastuzumab ± IM injection of fulvestrant until objective disease 
progression is documented or another criterion for discontinuation 
is met. 
Design 
 
This is an open-label, 3 + 3 dose-escalation and cohort-expansion, 
multicentre, Phase Ib study. At the time of Protocol version 4.0 is 
in force Step 1 (Dose-escalation Phase) has been completed. 
Step 1 (Dose-escalation Phase): A 3-cohort, ascending-dose 
(16 mg, 32 mg and 48 mg BID) design identified the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) 
of MEN1611 in combination with trastuzumab ±  fulvestrant The 
number of subjects per cohort were to be assigned according to a 
3 + 3 classical design, e.g., a minimum of 3 subjects in each dose 
cohort and if 1 of the first 3 subjects experiences a dose-limiting 
toxicity (DLT), 3 additional subjects were to be assigned to the 
same dose level. 
Step 2 (Cohort-expansion Phase): The RP2D will be confirmed in 
additional male and female subjects with PIK3CA mutant/HER2+ 
a/m breast cancer, in order to achieve a total of 30 subjects in each 
of the following treatment cohorts exposed to the MTD: 


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• HR-negative men and women, and HR-positive men and 
premenopausal women will be enrolled to receive 
MEN1611 + trastuzumab. 
• HR-positive postmenopausal women will be enrolled to 
receive MEN1611 + trastuzumab + fulvestrant. 
Step 2 will explore the preliminary anti-tumour activity of 
MEN1611 combined with trastuzumab ± fulvestrant with further 
assessment of their safety and tolerability. 
Note: Hormonal treatment such as GnRH analogs as per clinical 
local practice is allowed in HR-positive premenopausal women and 
male subjects assigned to receive MEN1611 + trastuzumab. 
DLT, MTD and RP2D 
definition 
An adverse drug reaction (ADR) in this study is defined as any 
adverse event (AE) suspected by the Investigator and/or the 
Sponsor to be related to MEN1611 when given in combination with 
trastuzumab ± fulvestrant. Toxicities will be graded according to 
the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.03 (NCI CTCAE v4.03), except for 
segmental wall-motion abnormalities (not described in NCI 
CTCAE v4.03). 
A DLT is defined as any of the following ADRs related to the 
combination regimens or to MEN1611 alone and unrelated to the 
subjects’ underlying disease or concomitant medication occurring 
during the DLT assessment period of 28 days: 
• Any grade 3 (lasting >7 days) or grade 4 increase in 
aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP). In subjects with hepatic 
metastases, AST or ALT >8x ULN or AST or ALT >5x 
ULN for ≥14 days is considered a DLT. In subjects with 
grade 2 AST, ALT, or ALP levels at baseline, an elevation 
to ≥ 10 × upper limit of normal (ULN) is considered a DLT.  
• Any grade 3 (lasting >7 days), or grade 4 if asymptomatic, 
increase in amylase and/or lipase. 


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• Any grade ≥3 cardiac toxicity or new segmental 
wall-motion abnormalities.  
• Any grade ≥3 non-hematologic toxicity with the following 
exceptions: 
o Nausea. 
o Vomiting. 
o Diarrhoea. 
o Skin rash. 
o Hyperglycaemia. 
Note: Nausea, vomiting and diarrhoea will be considered 
DLT if they are grade ≥3 for more than 72 hours with 
adequate antiemetic and other supportive care. Skin rash 
and hyperglycaemia will be considered DLT if they reach 
grade ≥3 despite adequate treatment as per the institution 
guidelines. 
• No recovery from a non-DLT relative to the above 
exceptions of grade ≥3 toxicity to grade ≤2 for more than 
14 days. 
• Febrile neutropenia (absolute neutrophil count [ANC] 
<1.0 × 109/L and fever ≥38.5°C) and/or documented 
infection with ANC <1.0 × 109/L. 
• NCI 
CTCAE 
v4.03 
grade 4 
neutropenia 
(ANC < 0.5 × 109/L) lasting ≥7 days. 
• NCI CTCAE v4.03 grade ≥3 thrombocytopenia (platelets 
< 50 × 109/L) with bleeding, lasting ≥7 days and grade 4 
thrombocytopenia (platelets <25 × 109/L) associated with 
or without non-traumatic bleeding, or bleeding requiring 
platelet transfusion. 
• Grade ≥3 fatigue lasting >1 week. 
• Grade ≥3 electrolyte abnormalities that last more than 72 
hours, unless the subject has clinical symptoms, in which 
case all grade ≥3 abnormalities regardless of duration 
should count as a DLT. 


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• Any NCI CTCAE v4.03 grade 4 (life-threatening 
consequences; urgent intervention indicated) anaemia 
lasting ≥7 days. 
• Any death not clearly due to the underlying disease or 
extraneous causes. 
• Final effective dose of MEN1611 is administered <80% 
and/or 
trastuzumab 
and/or 
fulvestrant 
are 
administered <100% of the total scheduled dose for safety 
reason. 
• Any other study treatment-related toxicity considered 
significant enough to be qualified as a DLT in the opinion 
of any of the Investigators. 
Throughout Step 1, although dose-escalation was primarily based 
on the incidence of DLTs during first 28 days of MEN1611 
administration1, toxicities that met criteria for DLTs and were 
observed over the overall treatment duration were taken into 
account for the assessment of toxicity and the definition of 
maximum dose judged to be tolerable. 
The MTD was defined as the highest dose level at which no more 
than 1 of 6 subjects experienced a DLT during the DLT assessment 
window (28 days). 
RP2D was defined as MTD or the maximum dose judged to be 
tolerable by the Safety Review Committee (SRC). 
Objectives 
Primary: 
• To determine the MTD and RP2D of MEN1611 when 
administered orally in combination with trastuzumab ± 
fulvestrant to adult subjects with PIK3CA mutated 
HER2-positive breast cancer pre-treated with at least 
2 anti-HER2 based therapy. 
Secondary: 
• To assess the safety and tolerability of MEN1611 in 
combination with trastuzumab ± fulvestrant. 


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• To assess the preliminary anti-tumor activity and clinical 
efficacy of MEN1611 in combination with trastuzumab ± 
fulvestrant.  
• To assess the pharmacokinetic (PK) profile of MEN1611 
when given in combination with trastuzumab ± fulvestrant. 


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Study Duration 
The overall study duration will depend on the completion of the 
escalating dose levels/cohorts, the number of subjects to be treated 
per each dose-cohort, the completion of the expansion cohort up to 
a total of 30 subjects in each of two treatment cohorts exposed to 
the MTD and the duration of subject’s response. 
All subjects pre-screened for the PIK3CA mutation will undergo a 
maximum 4-week Screening Period.  
Individual study duration will depend on the duration of the study 
treatment which continues up to disease progression or study 
discontinuation for other reasons. 
The End of Study Visit will be performed 4 weeks (± 7 days) after 
the last dose of MEN1611 or at the time of Study Withdrawal. 
Unscheduled assessments showing disease progression and leading 
to subject’s withdrawal can replace the End of Study Visit provided 
that all assessment/procedures scheduled for this visit are 
completed. 
After permanent withdrawal of the study treatment, subjects will be 
allocated to any other standard treatment as per the Investigator 
judgement. 
Survival Follow-up: 
After the End of Study Visit, all subjects evaluable for efficacy will 
be followed for survival status according to local practice (a visit or 
a telephone call) every 12 weeks ± 7 days up to the End of Study. 
End of Study: 
The study will end with the End of Study Visit of the last subject 
who discontinues the study treatment. For safety monitoring, all 
serious adverse events (SAEs) with a suspected causal relationship 
to the study treatment that occur after End of Study must be 
recorded and notified to the Sponsor as reported in section 8.6.2. 


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Inclusion Criteria 
The following criteria must be met in order to be eligible to entry 
into the pre-screening: 
1. Ability to give written informed consent. 
2. Being male or female aged ≥ 18 years. 
3. Histologically confirmed invasive adenocarcinoma of the 
breast. 
4. Known HER2-positive breast cancer status defined as 
immunohistochemistry (IHC) 3+; if IHC is 2+ or 1+, 
fluorescence in situ hybridisation (FISH) confirmation is 
required, according to current ASCO/CAP (American 
Society of Clinical Oncology - College of American 
Pathologists) 2018 guidelines. 
5. Known HR status (oestrogen receptor [ER] and/or 
progesterone receptor [PgR], with positivity defined as ≥1% 
immunoreactive tumor cell nuclei as per ASCO/CAP 2010 
guidelines on ER and PgR testing in breast cancer). 
6. Progression to at least one line of trastuzumab-based regime 
in the a/m setting and: 
• are on an ongoing second line of treatment or 
• have received at least 2 lines of HER2-targeted 
therapies. 
The following criteria must be met in order to be eligible to enter 
the study: 
1. Having written informed consent before any study-related 
procedure. 
2. Locally advanced or metastatic breast cancer harbouring a 
PIK3CA mutation, detected on the most recent archived 
FFPE tissue sample (or new tumour biopsy, if archived 
tumour tissue was not available) and centrally analysed by 
using validated Cobas® PIK3CA Mutation Test. 
3. Radiological documented evidence of progressive disease. 


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4. Known menopausal status at the time of the initiation of the 
study, if applicable. 
5. Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 0, 1 or 2. 
6. Life expectancy of ≥12 weeks. 
7. a) Having received at least 2 lines of anti-HER2-based 
regimens (e.g., pertuzumab, trastuzumab, lapatinib, and 
trastuzumab-entamsine 
[T-DM1]) 
in 
the 
advanced/metastatic (a/m) setting, including at least one 
regime containing trastuzumab. 
7.  b) ONLY for France: Having received at least 2 lines of 
anti-HER2 based regimens both in the advanced/metastatic 
(a/m) setting including at least one regimen containing 
trastuzumab and one regimen containing trastuzumab- 
entamsine (T-DM1). 
8. Adequate cardiac function as defined by left ventricular 
ejection fraction of ≥50%, measured by echocardiography 
or multi-gated acquisition [MUGA] scans. 
9. Adequate bone marrow function as defined by ANC of 
≥1.5 × 109/L, platelet count of ≥100.0 × 109/L, and 
haemoglobin of ≥9 g/dL. 
10. Adequate liver function as determined by total bilirubin 
within upper limit of normal (ULN) ≤1.5 × ULN (≤3 × ULN 
with direct bilirubin ≤1.5 × ULN in case of subjects with 
coexisting known Gilbert’s disease), and AST and ALT 
≤2.5 × ULN (≤5 × ULN if liver metastases). 
11. Adequate renal function assessed by creatinine ≤1.5 × ULN 
or creatinine clearance ≥50 mL/min (measured or calculated 
by Cockcroft-Gault formula). 
12. Not being pregnant or breastfeeding, nor being a woman of 
childbearing potential (WOCBP).  
Note: In case of being a WOCBP, she must agree to use 
highly effective contraception 4 weeks before the first dose 


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of the study treatment, during the treatment period, and for 
7 months following the last dose. Subjects should not 
breastfeed during the treatment period and at least for 
7 months after the last dose of the study treatment1. 
13. Being male subjects, surgically sterile or having agreed with 
true abstinence (must even refrain from heterosexual 
intercourse), and whose female partners are willing to agree 
with true abstinence or use barrier contraceptive measures 
during the entire study treatment period and for 3 months 
after the last administration of the study drug. Males must 
agree to refrain from donating sperm during the entire study 
treatment period and for 3 months after the last 
administration of the study drug. 
Postmenopausal subjects with HR-positive breast cancer who 
ALSO meet the following criterion will be eligible for entry into the 
study: 
14. International normalised ratio (INR) ≤ 2. 
Note: Inclusion criteria 5, 9 to 11 and 14 (if applicable) will be 
re-evaluated prior to the start of any study treatment (Day 1 of 
Cycle 1). 
Exclusion Criteria 
Subjects will not be eligible to participate in the study if they meet 
ANY of the following exclusion criterion: 
1. Previous treatment with 
PI3K 
inhibitor, 
mTOR 
or AKT inhibitor. 
2. Hypersensitivity and/or contraindication to MEN1611, 
trastuzumab or to any component of the formulations. 
3. Known HER2-negative breast cancer in all biopsies 
performed throughout the disease, defined according to the 
ASCO/CAP 2018 guidelines. 
                                                 
1 The period of contraception and restriction on breast feeding has been included to be consistent 
with the recommendations in the trastuzumab summary of product characteristics (SmPC) 


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4. Inability to swallow oral medications. 
5. Untreated brain metastases, with the exception of subjects 
with previously treated brain metastases (including 
radiation and/or surgery) >4 weeks earlier and only if 
clinically stable (as determined by the Investigator) and not 
receiving corticosteroids. 
6. History of clinically significant bowel disease including 
abdominal 
fistula, 
gastrointestinal 
perforation 
and 
diverticulitis. 
7. NCI CTCAE v4.03 ≥grade 2 diarrhoea, which is not 
resolved in the week prior to the start of study treatment 
(Day 1 of Cycle 1). 
8. History 
of 
significant, 
uncontrolled 
or 
active 
cardiovascular disease, specifically including, but not 
restricted to: 
• Myocardial infarction within 6 months prior to the first 
dose of the study treatment (Day 1 of Cycle 1). 
• Unstable angina within 6 months prior to first dose of 
the study treatment (Day 1 of Cycle 1). 
• Congestive heart failure (CHF) New York Heart 
Association Class III-IV. 
• Clinically significant atrial arrhythmia (including 
clinically significant bradyarrhythmia), as determined 
by the Investigator. 
• Long QT syndrome or other risk factors for “Torsades 
de Pointes” or increased QTc interval (QTc > 460 sec). 
• Ventricular arrhythmia.  
9. Cerebrovascular accident or transient ischaemic attack 
within 6 months prior to the start of the study treatment 
(Day 1 of Cycle 1). 
10. Uncontrolled hypertension (defined as persistent blood 
pressure [BP] of ≥150/90 mmHg despite treatment, 
measured on at least 2 separate occasions). 


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11. Known active or uncontrolled pulmonary dysfunction. 
12. Any serious and/or unstable pre-existing psychiatric or 
neurologic illness or other conditions that could interfere 
with subject’s safety. 
13. Uncontrolled diabetes mellitus (glycated haemoglobin 
[HbA1c] >7%) and fasting plasma glucose (FPG) 
>126 mg/dL. 
14. Known history of human immunodeficiency virus (HIV) 
infection or active infection with hepatitis C virus (HCV) 
or hepatitis B virus (HBV).  
15. Subjects diagnosed with another primary malignancy, 
except for: adequately treated non-melanoma skin cancer 
or cervical cancer in situ; or subjects with another primary 
malignancy who are definitively relapse-free for at least 
3 years since the diagnosis of the other primary 
malignancy. 
16. Concurrent chronic immunosuppressive treatment either 
with steroids or other immunosuppressive agents. 
17. Treatment with chemotherapy or immunotherapy (with the 
exception of anti-HER2 antibodies) within 21 days before 
the study treatment (Day 1 of Cycle 1). 
18. Therapeutic radiotherapy or major surgery within 28 days 
before the study treatment (Day 1 of Cycle 1); or limited 
field palliative radiation therapy within 2 weeks before the 
study treatment (Day 1 of Cycle 1). 
19. Any 
other 
concurrent 
severe 
and/or 
uncontrolled 
concomitant 
medical 
conditions 
(e.g., 
active 
or 
uncontrolled infection) that could cause unacceptable 
safety risks or compromise compliance with the protocol. 
 
 
 


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21. Treatment with any other investigational agent within 
28 days prior to starting the study treatment (Day 1 of 
Cycle 1) or within 5 half-lives of the investigational 
product, whichever is longer. 
22. Pregnant or breastfeeding women. 
23. Inability or unwilling to abide by the study protocol. 
Postmenopausal subjects with HR-positive breast cancer will not be 
eligible to participate in the study if they ALSO meet ANY of the 
following exclusion criteria: 
24. Hypersensitivity and/or contraindication to fulvestrant or to 
any component of the formulation. 
25. Any endocrine therapy for breast cancer (such as aromatase 
inhibitors or antioestrogens, with the exception of 
fulvestrant) within 28 days before the first administration 
of MEN1611 (Day 1 of Cycle 1). 
26. Warfarin sodium therapy or any other Coumadin-
derivative anticoagulant. 
27. Concurrent hormone replacement therapy. 
Study Procedures and 
Efficacy, Pharmacokinetic, 
Pharmacodynamic and 
Safety Assessments 
 
STEP 1 – completed (Dose-escalation phase)  
See APPENDIX I. 
STEP 2 (Cohort-expansion Phase) 
Study procedures for new subjects to be included at the time of this 
Protocol version 4.0 is in force (patients on 3-weekly trastuzumab 
administration schedule) are described below. 
For subjects already included in the study and that continue on 
weekly 
IV 
trastuzumab 
administration 
schedule, 
see 
APPENDIX I. 
Pre-Screening Period: 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
17 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
Subjects with HER2 positive a/m breast cancer will be eligible for 
pre-screening if they have progressed to at least one line of 
trastuzumab-based regimen in the a/m setting and: 
• 
are on an ongoing second line of treatment or 
• 
have received at least 2 lines of HER2-targeted 
therapies. 
At the Pre-screening Visit, all subjects will sign the informed 
consent to perform mutational analysis for PIK3CA and other 
relevant cancer genes on the most recent archived FFPE tissue and 
in plasma samples (for ctDNA sequencing, centrally analysed) . 
Eligibility to the study will be done based on PIK3CA mutations 
detected in FFPE tissue only. 
Note: In case no archived tissue sample is available, a new biopsy 
of the primary tumour or a metastasis should be obtained only upon 
subject consent, and based on the investigator’s judgment that there 
is no additional risk to the subject’s safety. The samples will be 
centrally analysed using validated Cobas® PIK3CA Mutation Test. 
Screening Period (Day -27 To Day -1): 
During the 28 days prior to the first dose of MEN1611 and 
following provision of written informed consent, each subject will 
be screened for eligibility. 
The following procedures will be performed at Screening: 
• Check of inclusion/exclusion criteria. 
• Recording of demographic data. 
• Standard medical, surgical and medication history. 
• Smoking history and current status. 
• Verification of pre- or postmenopausal status in 
HR-positive women. 
• Physical examination including vital signs (i.e., blood 
pressure 
[BP], 
heart 
rate, 
respiratory 
rate, 
body 
temperature), height and weight. 
• ECOG PS. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
18 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
• Recording of adverse events (AEs) and concomitant 
medications. 
• Baseline 12-lead electrocardiogram (ECG) record.  
• Baseline echocardiogram (ECHO) or MUGA scan. 
• Local Tumour assessment using Response Evaluation 
Criteria in Solid Tumours (RECIST) version 1.1 (v1.1) with 
computed tomography (CT) scan or magnetic resonance 
imaging (MRI) for subjects with measurable disease 
• Blood samples for haematology, coagulation and chemistry, 
HbA1c included. Blood sampling for anti-HIV antibodies, 
anti-hepatitis B core antigen (anti-HBcAg) antibodies, 
anti-hepatitis B surface antigen (anti-HbsAg) antibodies, 
HBV-DNA, HCV-ribonucleic acid (HCV-RNA). 
Note: In case the laboratory tests for anti-HIV antibodies, 
anti-HbcAg antibodies, anti-HbsAg antibodies, HBV-DNA 
and HCV-RNA have been performed within 3 months prior 
to Screening Period in the context of the standard subject’s 
management, these tests will not be repeated. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
• Optional new tumour biopsy upon subject’s consent and 
centrally analysed for PD.  
Note: Collection of tumour biopsy is recommended in 
order to confirm that the target inhibition is also occurring 
in the tumour. This should be particularly encouraged for 
tumours that can be readily biopsied. 
A screen failure is defined as follows: 
• A subject who does not meet the eligibility criteria required 
for study participation during the Screening Period. 
• A subject who no longer meets eligibility criteria at Day 1 
of Cycle 1. 
• A subject whose time window between Screening and 
Visit 1 (Day 1 of Cycle 1) is longer than 4 weeks. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
19 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
Note: If the complete assessment of the eligibility criteria is 
available within 3 days from the end of the Screening Period, the 
subject’s eligibility must be confirmed by the Medical Monitor. 
Screen failures can be re-screened upon Medical Monitor’s 
approval. A drop-out is defined as a subject who voluntarily 
withdraws from the study. 
Cycle 1: 
Visit 1 – Start of MEN1611 treatment (Day 1): 
(All assessments will be performed within 48 hours prior to 
administration of the study treatment, unless otherwise indicated) 
• Re-evaluation 
of 
inclusion/exclusion 
criteria 
and 
confirmation of subject’s eligibility prior to the start of the 
study treatment. 
• Tumour assessment using RECIST v1.1 with CT scan or 
MRI to be performed ONLY if the last assessment is older 
than 6weeks.  
• Physical examination including vital signs (i.e., BP, heart 
rate, respiratory rate, body temperature) and weight. 
• ECOG PS. 
• Blood sample for central analysis of tumour markers before 
the treatment: PIK3CA mutations in ctDNA and CTC 
enumeration. 
• 12-lead electrocardiogram (ECG) record (same technique 
used at screening): pre-dose and 2 hours post first daily 
MEN1611 dose administration. 
• Blood samples for haematology, coagulation and chemistry 
including HbA1c. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
 
 
 
 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
20 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
 
 
 
  
 
 
 
  
• Dispensing of the subject diary for study treatment 
compliance. 
• Recording of AEs and concomitant medications. 
• Cohort assignment for MEN1611 dose level (Step 1 only). 
• Study treatment administration, according to the following 
recommended order: 
o Trastuzumab IV dose of 6 mg/kg (over 30-minute). 
Alternatively  8 mg/kg (over 90-minute) dose 
(loading dose) could be administered instead, if 
considered appropriate by the investigator based on 
the time elapsed from the last trastuzumab dose prior 
to study enrolment.  
Note: Subjects will be monitored at the site for 
occurrence of AE for at least 2 or 6 hours after the 
start of trastuzumab 6 mg/kg or 8 mg/kg infusion, 
respectively. 
o Dispensing of MEN1611 and administration 
 
 of the first assigned dose (16, 32 or 
48 mg as 1, 2 or 3 capsule of 16 mg, respectively).  
o Fulvestrant 500 mg IM injection in HR-positive 
postmenopausal subjects. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
21 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
Visit 2 (Day 8), Visit 3 (Day 15)  
(All assessments will be performed within 48 hours prior to 
administration of the study treatment, unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart 
rate, respiratory rate, body temperature) and weight. 
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry. 
 
  
 
 
 
pre-dose (0 hours) and 2 hours after MEN1611 dose. 
• Recording of AEs and concomitant medications 
• Study treatment administration, according to the following 
recommended order: 
o Dispensing of MEN1611 and administration 
 
 at the assigned dose (16, 32 or 48 
mg as 1, 2 or 3 capsules of 16 mg, respectively). 
o Fulvestrant 500 mg IM injection in HR-positive 
postmenopausal subjects ONLY at Day 15 if the 
subject was not under fulvestrant treatment prior 
Cycle 1 Day 1. 
Cycle 2 Up To Cycle 4: 
Visit 1 (Day 1) (+3days window): 
(All assessments will be performed within 48 hours prior to 
administration of the study treatment, unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart 
rate, respiratory rate, body temperature) and weight. 
• ECOG PS. 
 
 
 
  


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
22 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
• 12-lead ECG record (same technique used at screening) at 
Cycle 2 (one pre-dose and one 2 hours post first daily 
MEN1611 dose administration , Cycle 3 Day 1 and Cycle 4 
Day 1  
• ECHO or MUGA scan (same technique used at screening) 
ONLY at Day 1 Cycle 3 (a time window of -7 days is 
allowed).  
• Blood samples for haematology, coagulation and chemistry 
including HbA1c. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
• Dispensing of the subject diary for study treatment 
compliance. 
• Recording of AEs and concomitant medications. 
• Study treatments administration, according to the following 
recommended order: 
o Trastuzumab 6 mg/kg will be administered as a 
30-minute IV infusion.  
Note: Subjects will be monitored at the site for 
occurrence of AE for at least 2 hours after the start 
of trastuzumab infusion. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
23 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
o Dispensing of MEN1611 and administration 
 
at the assigned dose (16, 32 or 48 
mg as 1, 2 or 3 capsules of 16 mg, respectively). 
Visit 2 (Day 8), Visit 3 (Day 15): 
(All assessments will be performed within 48 hours prior to 
administration of the study treatment, unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart 
rate, respiratory rate, body temperature) and weight. 
• ECOG PS. 
• Blood sample for central analysis of tumour markers before 
the treatment: PIK3CA mutations in ctDNA, and CTC 
enumeration at Day 8 of Cycle 2 and at Day 15 of Cycle 3 
• Blood samples for haematology, coagulation and chemistry. 
 
 
 
 
 
 
  
• Tumour biopsy will be performed on Day 15 (Visit 3) of 
Cycle 3 (±7 Days) only in subjects who underwent the 
optional assessment at screening, and centrally analysed for 
PD. 
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following 
recommended order: 
o Dispensing of MEN1611 and administration 
 
 at the assigned dose (16, 32 or 48 
mg as 1, 2 or 3 capsules respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal 
HR-positive subjects ONLY at Day 8 of Cycle 2 and 
Day 15 of Cycle 3 (i.e. every 4 weeks starting from 
Day 1 Cycle 1) 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
24 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
• Tumour assessment using RECIST v1.1 with CT scan or 
MRI will be performed every 8 weeks from the first 
MEN1611 administration (Day 1 Cycle 1) within a window 
of - 7 days.  
Cycle 5 Onwards: Visit 1 (Day 1) (+3 days window)  
(All assessments will be performed within 48 hours prior to 
administration of the study treatment, unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart 
rate, respiratory rate, body temperature) and weight. 
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry 
including HbA1c. 
• Serum pregnancy test (if applicable). 
• Blood sample for central analysis of tumour markers before 
the treatment: PIK3CA mutations in ctDNA, and CTC 
enumeration at Cycle 5 and every 2 Cycles   
• Sample for urinalysis. 
• 12-lead ECG (same technique used at screening) on Day 1 
of each Cycle.  
• ECHO or MUGA scan (same technique used at screeningto 
be performed on Day 1 Cycle 6 (- 7-day window) and on 
Day 1 of every third following cycle (e.g. Day 1 Cycle 9, 
Day 1 Cycle 12, Day 1 Cycle 15) 
• Dispensing of the subject diary for study treatment 
compliance. 
• Recording of AEs and concomitant medications to be 
integrated by weekly telephone call. 
• Study treatment administration, according to the following 
recommended order: 
o Trastuzumab 6 mg/kg as a 30-minute IV infusion. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
25 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
Note: Subjects will be monitored at site for 
occurrence of AE for at least 2 hours after the start 
of trastuzumab infusion. 
o Dispensing of MEN1611 and administration 
 
 at the assigned dose (16, 32 or 48 
mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in HR-positive 
postmenopausal subjects at Day 1 of Cycle 5 and 
every 4 weeks onwards 
 Tumour assessment using RECIST v1.1 with CT scan or MRI will 
be performed every 8 weeks from the first MEN1611 
administration (Day 1 Cycle 1) within a window of - 7 days Note: 
For the whole study duration, unscheduled visits can be performed 
when further assessments are required as per the Investigator’s 
judgement. 
End of Study Visit (4 weeks after last administered dose of 
MEN1611): 
• Physical examination including vital signs (i.e., BP, heart 
rate, respiratory rate, body temperature). 
• ECOG PS. 
• Smoking current status. 
• Tumour assessment using RECIST v1.1 will be performed 
if the last assessment is older than 8 weeks. 
• ECHO or MUGA scan (same technique used at screening), 
if not performed within the previous 14 days. 
• Blood samples for haematology, coagulation and chemistry. 
• Sample for urinalysis. 
• Recording of AEs and concomitant medications. 
• Serum pregnancy test (if applicable). 
• Blood sample for central analysis of tumour markers: 
PIK3CA mutations in ctDNA and CTC enumeration.  


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
26 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
Note: All subjects shall undergo the End of Study Visit on the 
scheduled day (at time frame of ± 7 days) or at the time of Study 
Withdrawal. Unscheduled assessment showing disease progression 
and leading to a subject’s withdrawal can replace the End of Study 
Visit, provided that all assessment/procedures scheduled for this 
visit are completed. 
Survival Follow-up: 
After the End of Study Visit, all subjects evaluable for efficacy will 
be followed for survival status according to local practice (a visit or 
a telephone call) every 12 weeks (±7 days) up to the End of Study. 
Laboratory Safety 
Parameters 
 
Blood safety laboratory tests: 
Blood safety laboratory tests will be performed at the local 
laboratory and will include: albumin, ALP, ALT, AST, blood urea 
nitrogen (BUN)/urea, creatinine, uric acid, sodium, chloride, 
potassium, phosphorus, calcium, total bilirubin, direct bilirubin, 
gamma-glutamyl transpeptidase (GGT), glucose, HbA1c, lactate 
dehydrogenase  
(LDH), total protein, prothrombin time and/or prothrombin activity, 
INR, partial thromboplastin time, amylase, lipase, platelets, red 
blood 
cells 
(RBC), 
mean 
corpuscular 
volume 
(MCV), 
haemoglobin, haematocrit, white blood cells (WBC) with 
differential (absolute and percentage) and beta human chorionic 
gonadotropin (β-HCG) (if applicable), anti-HIV Antibodies, anti-
HbcAg antibodies, anti-HbsAg antibodies, HBV-DNA and HCV-
RNA. 
Urinalysis: 
Urinalysis will be performed at the local laboratory and will 
include: pH, density, proteins, glucose, ketones and nitrite. 
Microscopy will be performed when required (i.e., RBC, WBC, 
epithelial cells, casts, bacteria, yeast and crystals). 
Study Endpoints 
Primary: 
Step 1 (Dose-escalation Phase): 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
27 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
• Identification of MTD, defined as the highest dose level at 
which no more than 1 of 6 subjects experiences a DLT 
during the DLT assessment window (see DLT and MTD 
definition). 
• Identification of DLT (see DLT definition). 
Step 2 (Cohort-expansion Phase): 
• Confirmation of RP2D defined as MTD or the maximum 
dose judged to be tolerable (see  RP2D definition). 
Secondary: 
• Response Rate defined according to RECIST v1.1 as per 
local radiology assessments and centralised blinded 
independent reading on  CT scan or MRI of the chest and 
abdomen (including pelvis and adrenal glands). Any other 
areas of disease involvement should be additionally 
investigated based on signs and symptoms of the individual 
subject.  
For the Baseline assessment, CT scan or MRI should be 
performed no more than 6 weeks before the start of study 
treatment. Follow-up assessment will be performed every 8 
weeks during study treatment starting from Day 1 Cycle 1 
(within a window of - 7 days) until objective disease 
progression as defined by RECIST v1.1 or at the End of 
Study Visit. Any other site at which a new disease is 
suspected should be appropriately imaged. If an 
unscheduled assessment is performed and the disease has 
not progressed, subsequent assessments should be 
performed at their scheduled visits. 
• Disease Control Rate (DCR) defined as percentage of 
subjects whose disease shrinks or remains stable over a 
certain time period. DCR is the sum of the complete 
response (CR), partial response (PR) and stable disease 
(SD) rates. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
28 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
• Duration of Response defined as time from confirmation of 
PR, CR or SD, until the disease has been shown to progress 
following treatment.  
• Progression-free survival (PFS) defined as the number of 
days between the first study treatment administration to the 
date of first documented disease progression, relapse or 
death from any cause. Responding subjects and subjects 
who are lost to follow-up are censored at their last tumour 
assessment date. 
• Overall Survival (OS) defined as the number of days 
between the first study treatment administration and death 
from any cause. 
Note: all secondary end points related to tumour assessment will be 
evaluated considering both local and central radiology assessments. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
29 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
Pharmacokinetic 
Endpoints 
The following PK variables will be assessed: 
Maximum observed plasma concentration (Cmax), time to Cmax 
(tmax), last quantifiable plasma concentration value (Clast), time to 
Clast (tlast), pre-dose plasma concentration (Ctrough), apparent 
terminal elimination rate constant (ke), terminal plasma half-life 
(t1/2), area under the plasma concentration-time curves from time 
zero (pre-dose) to the time of the last quantifiable concentration 
(AUC[0-t]), area under the plasma concentration-time curve from 
time zero to infinity (AUC(0-∞)), percentage of AUC(0-∞) obtained by 
extrapolation (%AUCex), apparent systemic clearance (CL/F), 
apparent volume of distribution at steady state (Vss/F), volume of 
distribution based on the terminal phase (Vd/F). PK parameters will 
be calculated after single and repeated dose administration. 
 
 
 
 
 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
30 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
 
 
 
Safety Endpoints 
 
Incidence, intensity, CTCAE version 4.03 grading, seriousness and 
treatment-causality of treatment emergent adverse events (TEAEs). 
Frequency of clinically significant abnormalities in physical 
examination, safety laboratory tests, urinalysis, vital signs, ECHO 
or MUGA scan and 12-Lead ECG (local review of traces). 
Sample size 
A maximum of 18 DLT evaluable subjects are needed to be 
enrolled in Step 1 (Dose-escalation Phase).  
During Step 2 (Cohort-expansion Phase), the RP2D will be 
confirmed in combination with trastuzumab and with trastuzumab 
and fulvestrant in HR-positive postmenopausal subjects in order to 
achieve a total of 30 subjects (considering also Step 1) in each of 
the treatment cohorts exposed to the MTD. 
Subjects who drop out prior to being evaluable for DLT during the 
Dose-escalation Phase will be replaced. Considering a 15% 
drop-out rate, approximately 80 subjects will be enrolled in the 
study. Due to the incidence of PIK3CA mutations and considering 
the drop-out rate, and the pre-screening and screening failure rates, 
around 600 HER2-positive a/m breast cancer subjects have to be 
pre-screened. 
Analysis populations 
DLT population: 
All subjects receiving at least 80% of MEN1611 and 100% of 
trastuzumab and/or fulvestrant during 28 days after the first 
MEN1611 drug administration with a Safety Follow-up of 28 days 
after the first administration of the study treatment. Any subject 
who experiences a DLT will also be considered evaluable. 
Subjects enrolled in the Dose-escalation Phase, who are not DLT 
evaluable will be replaced. 
Safety population: 
All subjects receiving at least 1 dose of MEN1611. 
Efficacy population: 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
31 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
All eligible subjects who receive at least 8 weeks of treatment nd 
have at least 1 disease assessment are to be considered evaluable 
for efficacy. 
PK population: 
All subjects receiving the study treatment and with reliable drug 
assay data relevant for the PK parameters of interest. 
Statistical analysis 
All study variables (with the exception of PK variables) will be 
presented by dose cohort and overall, using the appropriate 
descriptive statistics according to the variable nature, unless 
otherwise specified: 
• Continuous 
variables: 
Number 
of 
non-missing 
observations, 
arithmetic 
mean, 
standard 
deviation, 
minimum, median and maximum. 
• Categorical 
variables: 
Number 
of 
non-missing 
observations and column percentages (N, %). 
• Time to event variables: Number of non-missing 
observations, 
number 
and 
percentage 
of 
censored 
observations, 1st quartile, median (and its 95% confidence 
interval [CI]), 3rd quartile, Kaplan-Meier survival curves. 
The behaviour over time of study variables will be summarised by 
treatment cohort and overall as follows: 
• Continuous variables: descriptive statistics for each time 
point and for the absolute/percentage differences to 
baseline. 
• Discrete variables: descriptive statistics for each time point 
and shift tables to baseline. 
Correlation among subject’s variables will be evaluated calculating 
the appropriate correlation coefficient with the respective statistical 
significance level. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
 03 March 2022 
 
 
32 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
PK Analysis: 
PK analysis will be performed on the PK population. All PK 
variables (i.e., MEN1611 plasma concentrations and parameters) 
will be summarised by cohort using the following descriptive 
statistics: 
• Number of non-missing observations (N). 
• Arithmetic mean and its 90% CI, standard deviation, 
coefficient of variation (CV%) and standard error (SE). 
• Geometric mean (GM) and its 90% CI and GM CV%.  
• Minimum, median, maximum. 
MEN1611 plasma concentrations will be summarised for each 
scheduled sampling time point using descriptive statistics. 
Individual plasma concentration data versus time will be presented 
in a data listing and visualised as individual concentration-time 
plots. 
Analysis of exploratory PK/PD endpoints will be described in the 
Data Analysis Plan. 
 
 


Clinical Study Protocol  
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
33 of 168  
Confidential 
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Schematic Design: Dose-escalation and Cohort-expansion Study Design: 
 
 
DLT = dose-limiting toxicity, HER2+ = human epidermal growth factor receptor-2-positive, HR = hormone receptor, PI3K = Phosphatidylinositol/phosphoinositide 3-kinase, RP2D 
= recommended Phase 2 dose, SRC = Safety Review Committee  


Clinical Study Protocol  
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
34 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
 
Study Flow-Chart - Step 2 (Cohort-expansion Phase) for subjects on 3-weekly trastuzumab administration schedule 
PROCEDURE  
Pre-
screening 
Perioda 
Screening 
Period Day - 
27 to Day - 1 
Cycle 1 
Cycle 2 up to 4 
Cycle 5 
onwards  
End of 
Study 
Visitc 
Follow-
upk 
Visit 
1b 
Visits 
2b, 3b  Visit 1b 
Visits 
2b, 3b  
Visit 1b 
Day 1 
Days 
8, 15 
Day 1 
Days 8, 
15 
Day 1 
Day window 
  
  
  
  
+3 
  
+3 
  
  
Informed consent for PIK3CA mutational 
analysis on archived FFPE (or new tumour 
biopsy) and ctDNA 
X 
  
  
  
  
  
  
  
  
Informed consent 
  
X 
  
  
  
  
  
  
  
Inclusion/exclusion criteria 
  
X 
X 
  
  
  
  
  
  
Demographic data 
  
X 
  
  
  
  
  
  
  
Medical, surgical and medication history 
  
X 
  
  
  
  
  
  
  
Smoking history and/or current status 
  
X 
  
  
  
  
  
X 
  
Postmenopausal status in HR-positive subjects 
  
X 
  
  
  
  
  
  
  


Clinical Study Protocol  
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
35 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
PROCEDURE  
Pre-
screening 
Perioda 
Screening 
Period Day - 
27 to Day - 1 
Cycle 1 
Cycle 2 up to 4 
Cycle 5 
onwards  
End of 
Study 
Visitc 
Follow-
upk 
Visit 
1b 
Visits 
2b, 3b  Visit 1b 
Visits 
2b, 3b  
Visit 1b 
Day 1 
Days 
8, 15 
Day 1 
Days 8, 
15 
Day 1 
Day window 
  
  
  
  
+3 
  
+3 
  
  
Physical examination including vital signs 
  
X 
X 
X 
X 
X 
X 
X 
  
Weight 
  
X 
X 
X 
X 
X 
X 
  
  
Height 
  
X 
  
  
  
  
  
  
  
ECOG PS 
  
X 
X 
X 
X 
X 
X 
X 
  
12-lead ECGd 
  
X 
X 
  
X 
  
X 
  
  
Echocardiography or MUGAe 
  
X 
 
 
X 
 
X 
X 
  
Tumour assessmentf 
  
X 
X 
every 8 weeks from Day 1 Cycle 1 
X 
  
Optional new tumour biopsyg 
  
X 
 
  
 
X  
 
  
  
Blood sampling 
See “Blood and Urine Samples Flow Chart”, “PK Blood Samples Flow Chart” and 
“PD Hair Follicle and PRP Samples Flow Chart” (Sections 2.3, 2.4 and 2.5) 
  
  


Clinical Study Protocol  
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
36 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
PROCEDURE  
Pre-
screening 
Perioda 
Screening 
Period Day - 
27 to Day - 1 
Cycle 1 
Cycle 2 up to 4 
Cycle 5 
onwards  
End of 
Study 
Visitc 
Follow-
upk 
Visit 
1b 
Visits 
2b, 3b  Visit 1b 
Visits 
2b, 3b  
Visit 1b 
Day 1 
Days 
8, 15 
Day 1 
Days 
8, 15 
Day 1 
Day window 
  
  
  
  
+3 
  
+3 
  
  
Urinalysis 
  
X 
X 
  
X 
  
X 
X 
  
PD assessments 
See PD Hair follicle and PRP Samples Flow Chart (Section 2.5) 
  
  
Subject diary dispensing 
  
  
X 
  
X 
  
X 
  
  
MEN1611 dispensing 
  
  
X 
X 
X 
X 
X 
  
  
MEN1611 administration  
  
  
BID 
  
  
Trastuzumab administrationh 
  
  
X 
  
X 
  
X 
  
  
Fulvestrant administrationi 
  
  
X 
every 4 weeks from Day 1 Cycle 1 
  
  
AEs/concomitant medication 
  
X 
X 
X 
X 
X 
Xj 
X 
  
Overall survival 
  
  
  
  
  
  
  
  
X 
AE = adverse event, BID = twice daily, CT = computed tomography, ct = circulating tumour, CTC = circulating tumour cell, ECG = electrocardiogram, ECOG PS = Eastern 
Cooperative Oncology Group performance status, DNA = deoxyribonucleic acid, FFPE = formalin-fixed paraffin-embedded, HBcAg = hepatitis B core antigen, HbsAg = hepatitis 
B surface antigen, HBV = hepatitis B virus, HCG = human chorionic gonadotropin, HCV = hepatitis C virus, HIV = human immunodeficiency virus, HR = hormone receptor, 


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IM = intramuscular, MRI = magnetic resonance imaging, MUGA = multi-gated acquisition, PD = pharmacodynamic, PIK3CA = Phosphatidylinositol 3-kinase, catalytic, alpha 
polypeptide gene, PK = pharmacokinetic, PRP = platelet-rich plasma, RECIST = Response Evaluation Criteria in Solid Tumours, RNA = ribonucleic acid 
a. 
No time limits. The pre-screening will start as soon as the site is activated. 
b. All assessments will be performed within 48 hours prior to administration of the study treatment, unless otherwise indicated. 
c. 
End of Study Visit will be performed 4 weeks (± 7 days) after the last administered dose of MEN1611. 
d. 12 lead ECG will be performed at screening, at Cycle 1 Day 1 and Cycle 2 Day 1 (one pre-dose and one 2 hours post first daily MEN1611 dose administration) and then 
every 3 weeks prior trastuzumab administration.  
e. 
Echocardiography or MUGA will be performed at screening, on Day 1 of every third cycle and at the End of Study visit only if not performed within the previous 14 days. 
f. 
Tumour assessment will be performed using RECIST version 1.1 with CT scan or MRI according the schedule below. Imaging data will be also collected for retrospective 
central radiological evaluation by a blinded independent review committee.  
- 
Screening Visit: tumour assessment performed for subjects with measurable disease.  
- 
Cycle 1 Day 1: performed ONLY if the last assessment is older than 6 weeks. 
- 
From Cycle 1 Day 1 onwards: to be performed every 8 weeks (within a window of - 7 days). 
- 
End of Study Visit: performed only if the last assessment is older than 8 weeks.  
g. Optional new tumour biopsy will be performed upon subject’s consent and centrally analysed for PD during the screening visit. If performed at screening it will be repeated 
on Cycle 3 Day 15 and centrally analysed for PD. 
h. Starting from Cycle 1 Day 1, IV Trastuzumab 6 mg/kg will be administered every 3 weeks. On Cycle 1 Day 1, alternatively a loading IV dose of 8 mg/kg could be 
administered if considered appropriate by the Investigator. 
i. 
Fulvestrant 500 mg IM injection will be administered to HR‑positive postmenopausal subjects every 4 weeks from Cycle 1 Day 1; an additional dose will be administered 
on Day 15 of Cycle 1 if the subject was not under fulvestrant treatment prior Cycle 1 Day 1. 
j. 
After Cycle 5 Day 1, AEs/concomitant medication will be recorded weekly by telephone call.  
k. After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status according to local practice (a visit or a telephone call) every 12 weeks 
±7 days up to the End of Study.  


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Blood and urine samples flow chart – Step 2 (Cohort-expansion Phase) for subjects on 3-weekly trastuzumab 
administration schedule 
PROCEDURE  
Pre-
screening 
Perioda 
Screening 
Period 
Day - 27 
to Day - 1 
Cycle 1 
Cycle 2 up to 4 
Cycle 5 
onward  End of 
Study 
Visitc 
Follow-
upd 
Visit 
1b 
Visits 2b, 3b  
Visit 
1b 
Visits 2b, 
3b  
Visit 1b 
Day 1 
Days 8, 15 
Day 1 
Days 8, 15 
Day 1 
Day window 
  
  
  
  
+3 
  
+3 
  
  
Blood safety lab tests: 
haematology, coagulation, 
chemistrye 
  
Xf 
Xf 
X 
Xf 
X 
Xf 
X 
  
Serum Pregnancy test (if 
applicable) 
  
X 
X 
  
X 
  
X 
X 
  
Anti-HIV antibodies, 
anti-HbcAg antibodies, 
anti-HbsAg antibodies, 
HBV-DNA, HCV-RNA 
  
Xg 
  
  
  
  
  
  
  
ctDNA blood sampling 
X 
  
X 
  
Xh 
Xi 
X 
  
CTC blood sampling 
  
  
X 
  
Xh 
Xi 
X 
  


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ct = circulating tumour, CTC = circulating tumour cells, DNA = deoxyribonucleic acid, HbA1c = glycated haemoglobin, HBcAg = hepatitis B core antigen, HbsAg = hepatitis B 
surface antigen, HBV = hepatitis B virus, HCG = human chorionic gonadotropin, HCV = hepatitis C virus, HIV = human immunodeficiency virus, PD = pharmacodynamic,  PK = 
pharmacokinetic, PRP = platelet-rich plasma, RNA = ribonucleic acid 
a. 
No time limits. The pre-screening will start as soon as the site is activated. 
b. All assessments will be performed within 48 hours prior to administration of the study treatment, unless otherwise indicated.  
c. 
End of Study Visit to be performed 4 weeks (± 7 days) after last administered dose of MEN1611. 
d. After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status according to local practice (a visit or a telephone call) every 12 weeks ±7 
days up to the End of Study.  
e. 
Blood safety lab tests (haematology, coagulation, chemistry) will be performed in fasting condition, weekly up to Cycle 5 Day 1 and every three weeks afterwards (Day 1 of 
each Cycle). 
f. 
Blood safety lab tests including HbA1c analysis.  
g. There is no need to repeat these tests in case they have been performed within 3 months prior to Screening Period in the context of the standard subject’s management. 
h. ctDNA and CTC blood sampling only at Day 8 of Cycle 2 and Day 15 of Cycle 3. 
i. 
ctDNA and CTC blood sampling at Day 1 of Cycle 5 and then every 2 cycles. 
 
 


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3. STUDY ADMINISTRATIVE STRUCTURE 
Co-ordinating Investigator 
 
 
Institute Jules Bordet  
Boulevard de Waterloo 125 
B-1000 Brussels, Belgium 
E-mail:
 
Phone: 
 
Fax: 
 
 
Sponsor 
Menarini Ricerche S.p.A. 
Clinical Sciences 
Via Sette Santi, 1, 
50131 Florence, Italy 
 
Sponsor’s Representative 
 
E-mail: 
 
Phone: 
 
Fax: 
 
 
  
E-mail: 
 
Phone:  
 
Fax: 
 
 
 
E-mail: 
 
Phone: 
 
Fax: 
 
 
 
E-mail: 
 
Phone: 
 
Fax: 
 
  
(Medical Monitor) 
  
E-mail: 
 
Phone: 
 
Fax: 
 
Sponsor’s Pharmacovigilance Unit 
Laboratorios Menarini S.A. -Menarini Group 
Clinical Research 
C/ Alfons XII, 587 
08918 Badalona, Spain 
 
 
E-mail: 
 
Phone: 
  
Sponsor’s Pharmaceutical 
Manufacturer of the study treatment 
A. Menarini Research & Business Service GmbH  
Pharmaceutical Development Department 
Glienicker Weg 125 
12489 Berlin, Germany 


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E-mail: 
 
Phone:  
  
Fax: 
 
 
Clinical Research Organisation 
IQVIATM 
500 Brook Drive, Green Park, Reading, 
RG2 6UU (United Kingdom) 
 
 
E-mail:
 
Phone: 
 
Mobile: 
 
Details of all the laboratories will be provided in a separate Laboratory Manual. 


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4. TABLE OF CONTENTS 
 
1. 
SIGNATURES ........................................................................................................................... 2 
2. 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
 
Schematic Design: Dose-escalation and Cohort-expansion Study Design: ......................... 33 
 
Study Flow-Chart - Step 2 (Cohort-expansion Phase) for subjects on 3-weekly trastuzumab 
administration schedule .................................................................................................................. 34 
 
Blood and urine samples flow chart – Step 2 (Cohort-expansion Phase) for subjects on 3-
weekly trastuzumab administration schedule ................................................................................. 38 
 
 
 .............................................................................................. 40 
 
 
 .......................................... 41 
3. 
STUDY ADMINISTRATIVE STRUCTURE ......................................................................... 42 
4. 
TABLE OF CONTENTS ......................................................................................................... 44 
 
Abbreviations ........................................................................................................................ 49 
5. 
ETHICAL AND LEGAL ASPECTS ....................................................................................... 53 
 
General Aspects .................................................................................................................... 53 
 
Independent Ethics Committee and Legal Requirements ..................................................... 53 
 
Subject Information and Declaration of Consent ................................................................. 53 
 
Subject Insurance .................................................................................................................. 54 
 
Documentation of Study-related Data and Record Retention .............................................. 54 
 
Confidentiality ...................................................................................................................... 55 
 
Protocol/Protocol Modifications ........................................................................................... 55 
 
Study Commencement .......................................................................................................... 55 
 
Subject’s Safety .................................................................................................................... 55 
 Data Property/Publication Policy ......................................................................................... 56 
 Data Protection ..................................................................................................................... 57 
5.11.1 
General Principles on Personal Data Compliance ....................................................... 57 
5.11.2 
Acknowledgment ......................................................................................................... 57 
5.11.3 
Data Controllers and Data Processors .......................................................................... 57 
5.11.4 
Duties of the Parties involved in the Performance of the Study .................................. 58 
5.11.5 
Archiving of the clinical trial master file and subjects’ personal data ......................... 60 
5.11.6 
Data Breach .................................................................................................................. 61 
5.11.7 
Information Notice on Personal Data Protection and Pseudonymisation .................... 62 
5.11.8 
Genetic Data ................................................................................................................. 63 
5.11.9 
Transfer of subjects’ data outside the European Union ............................................... 65 
5.11.10 Exercise of subjects’ data privacy rights ...................................................................... 65 
5.11.11 Future Research............................................................................................................ 66 


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6. 
BACKGROUND INFORMATION ........................................................................................ 67 
 
Disease and Study Rationale ................................................................................................ 67 
 
PI3K Inhibitor in Cancer Therapy ........................................................................................ 68 
 
Investigational Medicinal Product: MEN1611 ..................................................................... 70 
6.3.1 
Physical, Chemical and Pharmaceutical Properties and Formulation .......................... 70 
6.3.2 
 ........................................................................................................ 71 
6.3.2.1 
 ..................................................................................... 71 
6.3.2.1.1 
 .......................................................................... 71 
6.3.2.1.2 
 ..................................................................................................... 72 
6.3.2.2 
 ....................................................... 72 
6.3.2.3 
 .................................................................................. 72 
6.3.3 
Clinical Experience ...................................................................................................... 74 
 
Risk Benefit Assessment ...................................................................................................... 75 
7. 
STUDY OBJECTIVES ............................................................................................................ 80 
 
Primary Objectives ............................................................................................................... 80 
 
Secondary Objectives ........................................................................................................... 80 
 
 ......................................................................................................... 80 
8. 
INVESTIGATIONAL PLAN .................................................................................................. 82 
 
Overall Study Design and Plan Description ......................................................................... 82 
 
Selection of Study Population .............................................................................................. 84 
8.2.1 
Inclusion Criteria.......................................................................................................... 84 
8.2.2 
Exclusion Criteria ........................................................................................................ 86 
8.2.3 
Withdrawal of Subjects from the Study or Discontinuation of the Study Treatment .. 88 
8.2.3.1 
Withdrawal from the Study ...................................................................................... 88 
8.2.3.2 
Subject Withdrawal from the Study Medication ...................................................... 89 
8.2.4 
End of Study................................................................................................................. 89 
 
Identity of the Investigational Products ................................................................................ 90 
8.3.1 
Description of Investigational Medicinal Products ...................................................... 90 
8.3.2 
Packaging, labelling and storage .................................................................................. 91 
8.3.3 
Drug accountability ...................................................................................................... 92 
8.3.4 
Destruction of the Study Treatment ............................................................................. 93 
 
Treatments ............................................................................................................................ 94 
8.4.1 
MEN1611 ..................................................................................................................... 94 
8.4.2 
Trastuzumab ................................................................................................................. 94 
8.4.3 
Fulvestrant .................................................................................................................... 95 
8.4.4 
Sequence of Study Treatment Administration ............................................................. 95 
8.4.5 
Treatment Compliance ................................................................................................. 96 


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8.4.6 
Management of Toxicities due to MEN1611 and Dosage Modification ..................... 96 
8.4.7 
Prohibited and Concomitant Medications .................................................................... 97 
8.4.8 
Dietary and Lifestyle Restrictions ................................................................................. 98 
 
Study Procedures and Assessments ...................................................................................... 98 
8.5.1 
Study Procedures for Step 1 and Step 2 ONLY for subjects who has started and 
continue on weekly trastuzumab administration schedule .......................................................... 98 
8.5.2 
Study Procedures for subjects on 3-weekly trastuzumab administration schedule ..... 98 
8.5.3 
Sample Handling & Shipping Management .............................................................. 105 
8.5.4 
Pharmacokinetics Procedure and Assessment ........................................................... 106 
8.5.5 
Pharmacodynamics Procedure and Assessment ........................................................ 109 
8.5.6 
Safety Assessment...................................................................................................... 110 
8.5.6.1 
Medical History ...................................................................................................... 110 
8.5.6.2 
Physical Examination and Vital signs .................................................................... 111 
8.5.6.3 
Weight measurement .............................................................................................. 111 
8.5.6.4 
Performance Status Evaluation .............................................................................. 111 
8.5.6.5 
Clinical Laboratory Evaluation .............................................................................. 112 
8.5.6.6 
12-Lead Electrocardiogram .................................................................................... 114 
8.5.6.7 
Echocardiogram (ECHO)/Multi-Gated Acquisition (MUGA) scan ...................... 114 
8.5.7 
Study Endpoints ......................................................................................................... 114 
8.5.7.1 
Primary Endpoints .................................................................................................. 114 
8.5.7.2 
Secondary Endpoints .............................................................................................. 116 
8.5.7.3 
 ............................................................................................ 116 
8.5.7.4 
Pharmacokinetic Endpoints .................................................................................... 117 
8.5.7.5 
Safety Endpoints..................................................................................................... 117 
 
Adverse Event Definitions, Monitoring/Recording and Management ............................... 117 
8.6.1 
Definitions .................................................................................................................. 117 
8.6.1.1 
Adverse Event (AE) ............................................................................................... 117 
8.6.1.2 
Drug Relationship................................................................................................... 118 
8.6.1.3 
Adverse Drug Reactions (ADRs) ........................................................................... 119 
8.6.1.4 
Seriousness ............................................................................................................. 119 
8.6.1.5 
Adverse Event (AE)/Adverse Drug Reaction (ADR) Intensity (Severity) ............ 120 
8.6.1.6 
Adverse Drug Reaction (ADR) Expectedness ....................................................... 120 
8.6.1.7 
Suspected Unexpected Serious Adverse Reaction (SUSAR)................................. 120 
8.6.2 
Monitoring and Recording of Adverse Events .......................................................... 121 
8.6.3 
Management of Serious Adverse Events (SAEs) ...................................................... 121 
8.6.3.1 
Reporting Duties of the Investigator ...................................................................... 121 
8.6.3.2 
Reporting Duties of the Sponsor ............................................................................ 123 
8.6.4 
Management of Non-Serious Adverse Events and/or Laboratory Abnormalities ..... 124 
8.6.5 
Management of Pregnancy Exposure Cases .............................................................. 124 
8.6.6 
Management of misuse and overdose cases ............................................................... 125 


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8.6.7 
Periodic Safety Reporting .......................................................................................... 125 
8.6.8 
Safety Issues other than SUSARs .............................................................................. 126 
8.6.9 
Breaking of the Randomisation Code ........................................................................ 127 
8.6.10 
Serious and Non-Serious Adverse Events Follow-up ................................................ 127 
 
Safety Review Committee .................................................................................................. 127 
8.7.1 
Blinded Independent Review Committee .................................................................. 127 
9. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...................... 128 
 
Determination of Sample Size ............................................................................................ 128 
 
Analysis Populations .......................................................................................................... 128 
 
Statistical Analysis .............................................................................................................. 128 
9.3.1 
Descriptive Statistics .................................................................................................. 128 
9.3.2 
Pharmacokinetic Analysis .......................................................................................... 129 
9.3.3 
Efficacy Analysis ....................................................................................................... 130 
9.3.4 
Safety Analysis .......................................................................................................... 130 
9.3.5 
Data imputations ........................................................................................................ 130 
 
Protocol Violations and Data Review Meeting .................................................................. 130 
 
Statistical Analysis Plan ..................................................................................................... 130 
10. 
DATA QUALITY MANAGEMENT .................................................................................... 132 
 Data Collection ................................................................................................................... 132 
10.1.1 
Electronic Case Report Form ..................................................................................... 132 
10.1.2 
Interactive Web-response System (IWRS) ................................................................ 132 
10.1.3 
Subject Diary.............................................................................................................. 133 
10.1.4 
Central Laboratory/Examination data ........................................................................ 133 
10.1.5 
Data Capture Systems Versions and Validation Documentation ............................... 133 
 Clinical Data Management ................................................................................................. 134 
 Source Data ......................................................................................................................... 134 
 Quality Control/Quality Assurance .................................................................................... 135 
10.4.1 
Study Monitoring ....................................................................................................... 135 
10.4.2 
Quality Assurance ...................................................................................................... 135 
11. 
PREMATURE TERMINATION OF THE WHOLE STUDY .............................................. 136 
12. 
END OF CLINICAL STUDY AND ARCHIVING .............................................................. 137 
 Archiving of Electronic Documentation/Data .................................................................... 137 
13. 
APPENDICES ....................................................................................................................... 138 
APPENDIX I: Study Procedures ONLY for subjects on weekly trastuzumab administration 
schedule ........................................................................................................................................ 138 
APPENDIX II: Contraceptive Guidance and Woman of Childbearing Potential ........................ 156 
APPENDIX III: 
 
................... 158 


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APPENDIX IV: Recommendations for Management of Toxicities related to MEN1611 ........... 160 
14. 
REFERENCES....................................................................................................................... 166 
 


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Abbreviations 
ABC 
Advanced breast cancer 
ADR 
Adverse drug reaction 
AE 
Adverse event 
Akt 
v-Akt murine thymoma viral oncogene homologue 
ALP 
Alkaline phosphatase 
ALT(SGPT) 
Alanine aminotransferase 
AMRBS 
A. Menarini Research & Business Service GmbH 
a/m 
Advanced or metastatic 
AST(SGOT) 
Aspartate aminotransferase 
ANC 
Absolute neutrophil count 
%AUCex 
Percentage of AUC(0-∞) obtained by extrapolation 
AUC(0-t) 
Area under the plasma concentration-time curves from time zero (pre-
dose) to the time of the last quantifiable concentration 
AUC(0-∞) 
Area under the plasma concentration-time curve from time zero to 
infinity 
AUCt 
Area under the plasma concentration-time curve from 0 to the last 
measurable concentration, computed using linear trapezoidal 
summation 
BC 
Breast cancer 
BP 
Blood pressure 
BID 
Bis in die, twice a day, twice daily 
BLOQ 
Below the lower limit of quantification 
BUN 
Blood urea nitrogen 
BIRC 
Blinded Independent Review Committee 
CA 
Competent Authority 
CI 
Confidence interval 
CL/F 
Apparent systemic clearance 
Cmax 
Maximum observed plasma concentration 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRO 
Contract research organisation 
CRF 
Case report form 
Ctrough 
Pre-dose plasma concentration 
CT 
Computed tomography 
CTC 
Circulating tumour cell 
CTM 
Clinical trial medication 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumour deoxyribonucleic acid 
CYP 
Cytochrome 
CV% 
Coefficient of variation 


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DCR 
Disease control rate 
DDI 
Drug-drug interaction 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DRM 
Data review meeting 
DSM 
Drug safety manager 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO  
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
ER 
Oestrogen receptor 
EU 
European Union 
FFPE 
Formalin-fixed, paraffin-embedded 
FIH 
First-in-human 
FISH 
Fluorescence in situ hybridisation 
FPG 
Fasting plasma glucose 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GM 
Geometric mean 
GnRH 
Gonadotropin-releasing hormone 
HbA1c 
Glycated haemoglobin  
HBcAg 
Hepatitis B core antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HER2 
Human epidermal growth factor receptor-2 
hERG 
Human Ether-à-go-go-related gene 
HIV 
Human immunodeficiency virus 
HR 
Hormone receptor 
HRT 
Hormone-replacement therapy 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
ID 
Identification 


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IHC 
Immunohistochemistry 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
INR 
International normalised ratio 
IRB 
Institutional review board 
IV 
Intravenous(ly) 
IWRS 
Interactive web-response system 
ke 
Apparent terminal elimination rate constant 
LDH 
Lactate dehydrogenase 
MBC 
Metastatic breast cancer 
MCV 
Mean corpuscular volume 
MRI 
Magnetic resonance imaging 
MRT 
Mean residence time 
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multi-gated acquisition scan 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
OS 
Overall survival 
p-Akt 
Phosphorylated Akt 
PD 
Pharmacodynamic/s 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PgR 
Progesteron-receptor 
PIK3CA 
Phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene 
PI3K 
Phosphatidylinositol/phosphoinositide 3-kinase 
PIP2 
Phosphatidylinositol 4,5-biphosphate 
PIP3 
Phosphatidylinositol (3,4,5)-trisphosphate 
PK 
Pharmacokinetic/s 
PR 
Partial response 
PRP 
Platelet-rich plasma 
PS 
Performance status 
PTEN 
Phosphatase and Tensin Homologue 
QA 
Quality assurance 
QD 
Quaque die, once a day, once daily 
RP2D 
Recommended Phase 2 dose 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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SAS 
Statistical Analysis System 
SD 
Stable disease 
SDSM 
Study Drug Safety Manager 
SE 
Standard error 
SmPC 
Summary of Product Characteristics 
SOP 
Standard operating procedure 
SUSAR 
Serious unexpected adverse reaction 
t1/2 
Terminal plasma half-life 
TEAE 
Treatment-emergent adverse event 
T-DM1 
Trastuzumab-DM1, trastuzumab emtansine 
tlast 
time to last quantifiable plasma concentration 
Tmax 
Time to reach maximum observed plasma concentration 
TTP 
Time to progression 
ULN 
Upper limit of normal 
Vd/F 
Volume of distribution based on the terminal phase 
Vss/F 
Apparent volume of distribution at steady state 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 


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5. ETHICAL AND LEGAL ASPECTS 
 
General Aspects 
This study will be carried out in compliance with the study protocol, the recommendations on biomedical 
research on human subjects of the Declaration of Helsinki, International Council for Harmonisation – 
Good Clinical Practice (ICH-GCP) Guidelines, European Union (EU) Directive 2001/20 April 04, 2001 
as amended and national requirements of the participating countries. 
The Sponsor has contracted the Contract Research Organisation (CRO), to perform some of the 
Sponsor’s study-related duties and functions (e.g., study initiation, clinical conduct, medical writing, 
monitoring and termination and project management). The Sponsor will perform study planning and 
preparation, medical monitoring and safety management, data management, statistical analysis, medical 
writing and quality management. The ultimate responsibility for the quality and the integrity of the study 
resides with the Sponsor. The study will be conducted in agreement with Sponsor’s or CRO’s Standard 
Operating Procedures’ (SOP) requirements as agreed. 
All clinical work conducted under this protocol is subject to GCP rules. This includes audits/inspections 
by the Sponsor and/or its delegate (e.g., CRO) and/or by national/international Health Authority 
representatives at any time. All Investigators must agree to the audits/inspection of the study site, 
facilities and of study-related records by the Health Authority representatives and/or by the Sponsor 
and/or its delegates, which must be performed in accordance with national laws concerning personal data 
protection. 
 
Independent Ethics Committee and Legal Requirements 
Before starting the study at a study site, the study protocol and relevant documentation must be submitted 
to and approved by the Institutional Review Board/Independent Ethics Committees (IRB/IEC) and the 
Competent Authorities (CAs) of the participating countries. 
In addition, all local national legal requirements for the conduct of a clinical study have to be followed 
prior to the start of the study. The CAs and IRB/IECs of the participating countries will be informed 
about any changes in the study protocol, the end of the study, or the premature study termination as 
appropriate and within the requested time period.  
 
Subject Information and Declaration of Consent 
Before any study-related procedures may be performed, informed consent must be obtained from the 
subject by means of a signed declaration. 
The Informed Consent Form (ICF) must be approved in the corresponding local language and in 
accordance with local laws and regulations by the IRB/IEC prior to being submitted to the subject. 


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In the subject information leaflet, subjects will be given information and a fully comprehensive 
explanation in easily understandable terms of the study procedures, regarding the benefits, discomforts 
and risks in taking part in the study, the properties of the study treatment, the method of assignment to 
treatments and any medically accepted and readily available treatment other than the study treatment. 
Subjects will also be informed about the measures taken to ensure their confidentiality according to the 
pertinent legislation.  
After being duly informed and interviewed by the Investigator, the subject has to freely date (including 
time) and sign the ICF in duplicate before being enrolled into the study and before undergoing any study 
procedure. The Investigator must store one original of the signed ICF in the Investigator’s File and the 
subject will be provided with the other one. The process of obtaining the ICF has to be documented in 
the source documents. 
If a protocol amendment would affect the terms of the ICF, it will be revised to reflect the protocol 
change and submitted to IRB/IEC for approval. The Investigator will ensure that this new consent form 
is signed by all subjects subsequently entered in the study and those currently in the study, before the 
changes take effect on their participation in the study. Subjects who do not sign the new consent form 
need to be terminated from the study participation. 
 
Subject Insurance 
For subjects participating in the study, the Sponsor, Menarini Ricerche S.p.A. has stipulated an insurance 
policy in accordance with local regulatory requirements. 
Details on the insurance company, the insurance number and conditions will be made available to 
subjects in the ICF and/or provided as a separate document, in accordance with national requirements. 
A copy of the insurance certificate will be provided to each Investigator and will be filed in the 
Investigator’s File at the sites and in the study’s Trial Master File (TMF). 
 
Documentation of Study-related Data and Record Retention 
It is the responsibility of the Investigator to document all study-related data for each subject in a case 
report form (CRF). For this study, an electronic CRF (eCRF) will be used. The Investigator has to 
guarantee the accuracy of the documented data and has to comment on any missing or spurious data. 
In addition to the eCRF, the Investigator will maintain adequate records that fully document the 
participation of the subject in the clinical study, including the study assessments (subject source data 
documentation). Details on the source data documentation are provided in Section 10.3.  
Requirements for record retention are specified in section 5.11.5. 


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No study documents should be destroyed without prior written agreement between the Sponsor and 
Investigator. Should the Investigator wish to move the study record to another location, he/she must 
notify the Sponsor in writing. 
 
Confidentiality 
By signing the study protocol, the Investigator affirms that any information provided by the Sponsor will 
be maintained in confidence and that such information will be divulged to IRB/IECs or CAs only under 
an appropriate understanding of confidentiality with such a committee or institution. 
In order to maintain the subject’s confidentiality, all data collected by the Investigator will be recorded 
pseudonymously in the eCRF. Subject’s data will be identified by a unique subject number. The 
Investigator must agree that within national regulatory restrictions and ethical considerations, 
representatives of the Sponsor, any regulatory agency and IRB/IEC may consult study source documents 
in order to verify data in the eCRF. Subject medical records pertinent to the study will be reviewed by 
the Study Monitor to ensure adequate source documentation, accuracy and completeness of eCRFs. The 
review will be conducted in accordance with relevant SOPs and with strict adherence to professional 
standards of confidentiality, GCP and the relevant data protection legislation. 
 
Protocol/Protocol Modifications 
The protocol must be read thoroughly by everyone, the information therein, concerns and the instructions 
must be exactly followed. 
Changes in the study protocol will require a protocol amendment. Such amendments will be agreed upon 
and approved in writing by all Signatories of the protocol. If amendments are substantial, i.e., they are 
likely to have an impact on the safety of the subjects, or to change the interpretation of the scientific 
documents in support of the conduct of the study, or if they are otherwise significant, the IRB/IECs and 
the CAs in the participating countries have to approve these amendments before implementation.  
Changes which have no significant impact on the medical or scientific validity of the study will be agreed 
upon and approved in writing by all signatories of the protocol and the IRB/IECs and the CAs will be 
notified of this protocol amendment. 
 
Study Commencement 
The study can commence at an individual study site only after all prerequisites are fulfilled according to 
ICH/GCP guidelines, any local regulatory requirements and the Sponsor/CRO’s SOPs. 
 
Subject’s Safety 


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If any event(s) related to the conduct of the study or the development of the study treatment affects the 
safety of the study participants, the Sponsor and the Investigator will take appropriate urgent safety 
measures to protect the subjects against any immediate hazard. The CAs and IRB/IECs will be informed 
forthwith about these new events and the measures taken. 
 Data Property/Publication Policy 
All data generated in the study (e.g., eCRFs, subject diaries, the structured data files in the clinical 
database system, the results of the statistical evaluation and medical interpretation as well as the final 
clinical study report) are the property of Menarini Ricerche S.p.A. 
It is intended that the study design and main results will be published on www.clinicaltrials.gov and on 
other applicable websites (e.g., https://www.clinicaltrialsregister.eu). In addition, the results of the study 
may be published as scientific literature. Results may also be used in submissions to CAs. The conditions 
mentioned below are intended only to protect confidential commercial information (patents, etc.) and 
not to restrict publication. 
All information concerning MEN1611 (such as patent applications, formulas, manufacturing processes, 
basic scientific data, or formulation information supplied to the Investigator by Menarini Ricerche S.p.A. 
and not previously published) is considered confidential by Menarini Ricerche S.p.A. and will remain 
the sole property of Menarini Ricerche S.p.A. The Investigator must agree not to use it for other purposes 
without written consent from Menarini Ricerche S.p.A. 
Menarini Ricerche S.p.A. will use the information obtained in this clinical study in connection with the 
development of MEN1611 and therefore may disclose it to other Investigators or concerned CAs in the 
EU or abroad. In order to allow for the use of information derived from this clinical study, the 
Investigator has an obligation to provide Menarini Ricerche S.p.A. with complete test results and all data 
recorded during this study. 
Prior to submitting the results of this study for publication or presentation, the Investigator will allow 
Menarini Ricerche S.p.A. at least 60 days’ time to review and comment upon the publication manuscript. 
Menarini Ricerche S.p.A. will provide any manuscript of the results of this study to the authors at least 
30 days before submission for a complete review. In accordance with generally recognised principles of 
scientific collaboration, co-authorship with any Menarini Ricerche S.p.A. personnel will be discussed 
and mutually agreed upon before submission of a manuscript to a publisher. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster exhibition 
or publication by the Investigator until Menarini Ricerche S.p.A. has reviewed/commented and agreed 
to any publication. 


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 Data Protection 
5.11.1 General Principles on Personal Data Compliance 
All clinical trial information shall be recorded, processed, handled, and stored in such a way that it 
can be accurately reported, interpreted and verified; at the same time, the confidentiality of records 
and of the personal data of the subjects shall remain protected in accordance with the applicable law 
on personal data protection such as the EU General Data Protection Regulation 679/2016 and the EU 
Regulation on clinical trials on medicinal products for human use 536/2014. 
This section defines the appropriate technical and organisational measures that shall be implemented 
to protect information and personal data processed against unauthorised or unlawful access, 
disclosure, dissemination, alteration, or destruction or accidental loss as well as to assure the 
fulfilment of subjects’ privacy rights. 
5.11.2 Acknowledgment 
The Site, the Principal Investigator, the Central Laboratories, the CRO as well as their appointed staff 
and service providers acknowledge that:  
(a) 
The performance of the study will imply processing of sensitive personal data; 
(b) 
Personal data processing is regulated by the applicable European (i.e. the EU General Data 
Protection Regulation 679/2016 and the EU Regulation on clinical trials on medicinal products for 
human use 536/2014) and local laws (i.e. the laws of the country where the study is conducted) as 
well as by the Sponsor’s national legislation. In particular, it is hereby acknowledged that being the 
Sponsor a company incorporated under Italian law, it has to mandatorily comply with Italian legal 
provisions on data protection: therefore, the Site, the Principal Investigator, the Central Laboratories, 
the CRO shall cooperate with the Sponsor to allow the fulfilment of such obligations; 
(c) 
Strict compliance with the applicable data protection laws and this section of the protocol is 
deemed by the Sponsor as an essential condition of collaboration with the Site, the Principal 
investigator, the Central Laboratories, and the CRO. 
5.11.3 Data Controllers and Data Processors  
The Sponsor, the Site, the Principal Investigator and the CRO acknowledge that according to the 
applicable privacy laws, Sponsor and Site will act as independent data controllers while CRO and the 
Principal Investigator will act as data processors respectively of the Sponsor and of Site. Before the 
beginning of the study, the Site will instruct in writing Principal Investigator as its data processor. 
However, if specific local laws or regulations mandate a different definition of the privacy roles, The 
Sponsor, the Site, the Principal Investigator and the CRO will implement the relevant legal 
instruments (e.g. if pursuant to the local laws the Site is a data processor of the Sponsor, a Data 


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Processing Agreement will be finalised; if pursuant to the local laws Sponsor and Site are join 
controllers, a Joint Controllership Agreement will be finalised). 
5.11.4 Duties of the Parties involved in the Performance of the Study 
Collection and use of subjects' personal data (i.e. subjects' data), including their biological samples, 
will be carried out in full respect of the provisions of the information notices submitted to subjects, 
as well as the privacy rights, the fundamental freedoms and the dignity of data subjects. All the parties 
involved in this study undertake to adopt adequate measures to warrant that data will always be 
processed securely and in compliance with privacy laws. 
The Site, the Principal Investigator, the Sponsor, the CRO and the Central Laboratories as well as 
their appointed staff and service providers, each in its respective remit and within the limits of their 
specific role in the study shall implement the following safety measures (physical, logical, 
organizational, technical, electronic, IT, etc…) to ensure adequate protection of the personal data of 
the subjects involved in the study. In particular: 
(i) 
Data Safety. The Site and/or the Principal Investigator shall adopt all the necessary measures 
to prevent or minimise the risks of theft, fire, flooding, partial or total loss, accidental disclosure or 
illegal/unauthorised access to subject’s data or Sponsor’s proprietary confidential information; to this 
extent, before the beginning of the study, the Site and/or the Principal Investigator shall ensure that 
the actual measures they have implemented are fit-for-purpose and law-compliant, and in particular: 
• in order to minimise the risk of unauthorized access and theft, the hardware on which 
subjects’ personal data are stored shall be placed in a restricted-access area, accessible 
only to those individuals who need to retrieve the subjects’ personal data included in the 
database for professional purposes; the same safeguards shall be put in place for non-
electronic databases; 
• any electronic database containing the subjects’ personal data shall be password-protected 
by means of a strong password. Systems shall be set so that passwords must be updated at 
least every three months and feature at least 8 characters, with upper-case and lower-case 
recognition, containing at least three "special" characters, such as upper case letters [A-
Z], lower case letters [a-z], numbers [0-9], symbols [!, #, $, etc.] or other special characters 
[Á, ë, ö etc.]. Passwords shall not include elements which may easily be associated with 
the assignee or information regarding him/her, such as name and year of birth (e.g. 
“johnbrown80”) or easily predictable strings of characters (e.g. “qwerty”, “12345”, 
“admin”, “user”, etc.)  


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• adequate cryptographic protection measures shall be put in place for data “at rest” and “in 
transit” (these include, for example, file system or database cryptography, or any other 
equivalent IT measure which renders data unintelligible to those who are not authorised 
to access them);  
• high level security measures shall be implemented also on the files or databases which 
contain the “key” to match the subjects’ personal data (i.e. name, surname, etc.) with their 
respective “Subject IDs” (as defined at point (iv) below); 
• backup processes and other measures that ensure rapid restoration of business critical 
systems shall be implemented; 
• updated antivirus and firewall programs shall be installed on the IT devices. 
The Site shall regularly test and update the measures listed above.  
The Site shall, upon request from the Sponsor and/or the CRO, provide detailed written information 
about the measures listed above.  
The CRO shall ensure that the selected sites for the study have implemented the above listed 
measures.  
(ii) Transmission Of Data. All the parties that transfer data through internet and/or to the centralised 
database(s) used to process study’s data or to generate statistical analyses shall implement secure 
protocols based on cryptographic standards which make data unintelligible to unauthorized 
individuals. 
(iii) 
Security Of The Centralised Data Base. The centralised database held by the Sponsor shall 
have the following safeguards in place:  
• appropriate authentication methods, which differentiate between different users according to 
their respective roles so as to ensure that access to a specific set of subjects' data is permitted 
exclusively to those for whom access to such data is essential in the context of their work for 
the study; 
• appropriate measures to ensure that the authentication credentials are periodically updated (i.e. 
password change); 
(iv) 
Pseudonymisation. All personal data that may allow identification of the subjects involved 
in the study shall be adequately dissociated from the other data pertaining to the study (“pseudo-
anonymisation” process). The Principal Investigator shall adequately dissociate the identification data 
of subjects from the data pertaining to the study by linking results to a an alphanumerical code 
“Subject ID”, whose format shall not make it possible to identify the subject directly or indirectly, so 


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as to ensure that only anonymous data are transmitted to the Sponsor, the Central Laboratories and 
/or the CRO. The Site/Principal Investigator shall securely store a separate list (e.g: identification log) 
with the identification code, together with all signed informed consents, in accordance with the 
security measures as defined above.  
(v) 
Sample Storage. As outlined below, samples shall only be stored for as long as strictly 
necessary for the study’s performance and will be stored for up to 10 years after the end of the clinical 
research study. Biological samples and any other examination (e.g. X-ray, ECG) shall bear Subject 
ID, and in no case will they bear other information that may lead to the direct or indirect identification 
of the subject, especially when, in accordance with this protocol, samples shall be forwarded and 
shared outside the clinical Site (eg. in case of centralized reading or local laboratory analysis).  
(vi) 
Training. The parties shall ensure that any personnel involved in the study have received 
proper training on data protection issues. 
All actions related to the implementation of the aforementioned measures shall be provided by the 
Sponsor, the Site and/or the CRO to the Competent Authorities (including data protection authorities) 
and Ethics Committees if and when requested. If such authorities or the Sponsor consider the 
implementation of the afore mentioned measures insufficient to guarantee an adequate level of 
protection of the subjects’ personal data, The Site, the Principal Investigator, the CRO and the Central 
Laboratories undertake to adopt all the necessary activities to overcome such remarks to assure the 
full compliance with the data protection laws. 
5.11.5 Archiving of the clinical trial master file and subjects’ personal data 
Unless other countries laws require archiving for a longer period, the Sponsor, the Site and the 
Principal Investigator shall archive the content of the clinical trial master file, including the relevant 
subjects’ personal data, for at least 25 years after the end of the clinical trial. However, medical 
records and the identification code list (i.e. the list that where the Subject ID is linked to the subjects’ 
identification data such as name and surname), including the relevant subjects’ personal data, shall 
be archived in accordance with the national laws of the country where the study is performed. 
The content of the clinical trial master file shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. 
Any transfer of ownership of the content of the clinical trial master file shall be documented. The new 
owner shall undertake the responsibilities set out in this protocol. 
The Sponsor appoints the study manager or delegates as responsible person/s for archives. Access to 
archives shall be restricted to those individuals. 
The media used to archive the content of the clinical trial master file shall be such that the content 
remains complete and legible throughout the period referred to in the first paragraph. Any alteration 


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to the content of the clinical trial master file shall be traceable. Once mandatory data retention time 
for the clinical trial master file has elapsed, the Centre/Principal Investigator shall seek the 
authorisation of the Sponsor to destroy the clinical trial master file. 
5.11.6  Data Breach  
Data Breach is an incident regarding personal data security and leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, stored 
or otherwise processed. In particular: destruction of personal data is where the data no longer exists, 
or no longer exists in a form that is of any use to the Site, Sponsor, CRO, Principal Investigator etc; 
data loss is when the data may still exist, but the Site, Sponsor, CRO, Principal Investigator etc. has 
lost control or access to it, or no longer has it in its possession; damage is where personal data has 
been altered, corrupted, or is no longer complete; data unavailability is where, following a data 
incident (such as a network outage, a natural or man-made disaster, etc.), personal data become 
temporarily inaccessible to the Site, Sponsor, CRO, Principal Investigator etc.  
Anomalous Event is an event that is not part of the standard operational scope of an infrastructure, 
network or service and which affects, or is likely to affect, personal data; this may include theft or 
loss of IT devices and other physical events (e.g. an unauthorised access to a locked storage room 
containing paper files with personal data), and/or electronic/IT anomalies (e.g. cyber-attacks, default 
or hacking of cloud services), which may in any way entail loss, unavailability, alteration, theft, copy 
or dissemination of personal data.  
Whoever becomes aware in any way of an Anomalous Event and/or of a Data Breach (see definitions 
above) affecting the subjects’ personal data and/or personal data collected in the context of the study 
shall, as appropriate, immediately (and in any case no later than 24 hours from the knowledge of an 
Anomalous Event and/or of a Data Breach) inform the study manager, the sponsor’s Data Protection 
Officer, who may be contacted at dpo@menarini.com or dpo.germany@berlin-chemie.de, the Site 
and the CRO [
 
IQVIA, PrivacyOfficer@iqvia.com] and shall provide the following information:  
(i) Anomalous Event/Data Breach Type (e.g. data loss, unauthorized access, loss of company device, 
etc.);  
(ii) Person or source that first reported the Anomalous Event/Data Breach; 
(iii) Date and Time when the person who first reported the Anomalous Event/Data Breach became 
aware of it; 
(iv) Anomalous Event/Data Breach Date and Time (actual or presumed); 
(v) Place (specify if actual or alleged) where the Anomalous Event/Data Breach occurred ; 
(vi) Anomalous Event/Data Breach Description;  


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(vii) Indicate the source of the Anomalous Event/Data Breach (e.g. I.P. source) - (if relevant); 
(viii) Indicate the affected infrastructure/system/application/cloud/software/hardware/database and 
their location; 
(ix) List or describe the processing/storage systems affected by the Anomalous Event/Data Breach (if 
relevant); 
(x) Number of data subjects involved (if known); 
(xi) Amount of allegedly breached data  
(xii) Other relevant information 
Once all the above information have been provided, the Sponsor and/or the Site should have a 
reasonable degree of certainty that a security incident has occurred that has led to personal data being 
compromised.  
Then, as appropriate, the Sponsor and the Site each one in its respective remit, shall manage the Data 
Breach in accordance with the applicable data protection regulations. 
For Data Breach affecting personal data of subjects enrolled within the European Union, Sponsor and 
Site autonomously or jointly -depending on the circumstances and their privacy responsibilities as 
defined by the Regulation 679/2016- shall:  
1. collect the necessary evidence and information; 
2. categorise the breach; 
3. determine the risk probability and level to the rights and freedom of the concerned subjects; 
4. identify and put in place appropriate remedies to minimise the impact of the Data Breach; 
5. determine the notification and communication duties vis à vis the competent supervisory 
authority and/or the concerned subjects. 
 
5.11.7 Information Notice on Personal Data Protection and Pseudonymisation  
Prior to subjects’ enrolment in the study, the Principal Investigator and/or the Site (including their 
personnel) shall provide each subject with adequate, law-compliant “information notices and consent 
forms to process personal data” as included in the ICF (or, as the case may be, through a separate, 
specific form) provided by the Sponsor or delegated CRO and shall collect subject’s written consent 
to the processing of personal data according to the actual performance conditions in which the study 
is carried out. The Principal Investigator is responsible to archive the signed ICF in accordance with 
the security measures described above. 
Among other things, the ICF (or the separate form) shall inform subjects about:  
(i) the applicable data protection legislation; 
(ii) what kind of data shall be collected during the study listing them in detail or by category; 


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(iii) the purpose of data processing (for the performance of the study and/or for pharmacovigilance 
purposes and/or to register new medicines) and the legal basis; 
(iv) whether granting the consent(s) to process personal data is a necessary or an optional condition 
to take part in the study;  
(v) the use of data for future scientific researches/secondary use of data (if any). In such a case the 
future scientific purposes/secondary use shall include retrospective clinical studies, clinical studies 
pertaining to your pathology/medical condition(s), and studies aimed at evaluating new medicine; 
(vi) the pseudonymisation procedure and scope; 
(vii) who can access subjects’ data and under what circumstances (Principal Investigator and site for 
the study conduction, Sponsor for analysis of data, regulatory authorities for registration of new 
medicine and/or for inspections, and the central laboratories. The complete list will be available upon 
request); 
(viii) the period of data retention/storage as defined in § 5.11.5 above, including the storage of the 
biological sample (see § 8.2.4); 
(ix) to which entities/countries outside the EU subjects’ data will be transmitted, (including but not 
limited to USA). The complete list will be available upon request. 
(x) subjects’ data protection rights as defined by the EU General Data Protection Regulation 
679/2016; 
(xi) Data Controllers/Data Processors and the relevant contact details; 
(xii) Sponsor’s Data Protection Officer contacts (dpo@menarini.com or dpo.germany@berlin-
chemie.de); 
(xiii) in case of genetic data processing the possible findings, also with regard to unexpected findings 
that might be disclosed on account of the processing of the genetic data. 
5.11.8 Genetic Data  
• The collection of genetic data for performing genetic tests and screening shall be limited to 
the personal and family information that is absolutely indispensable for performing the study. 
• If genetic data are processed in the context of the study for pregnancy follow-up purposes 
(pharmacovigilance) only (i) the collection of genetic data for performing genetic tests and 
screening shall be limited to the personal and family information that is absolutely 
indispensable for pregnancy follow-up; (ii) the source, nature and mechanism for samples 
taking and storage will be under the pregnant health care provider and its local procedures; 
genetic data shall be processed pursuant to the applicable pharmacovigilance laws and 


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regulations; genetic data shall be communicated/transmitted using high security standard. The 
provisions below shall be implemented as applicable from time to time. 
• The source, nature and mechanisms for samples taking and storage as defined in § 8.2.4 and 
§ 8.5.2. 
• Without prejudice to applicable laws and regulations, except for data and results as per § 5.10, 
the protocol shall be subject to confidentiality obligations that will assure the secrecy of the 
data for at least one year after the conclusion of the study. 
• The measures to keep subjects’ identification data separated from biological materials and 
genetic information are reported in §5.11.4 and § 5.11.5. 
• Access to the premises where genetic data are stored shall be controlled by security staff 
and/or electronic devices also based on biometrics. Any person admitted after closing time, 
on whatever grounds, shall have to be identified and their data recorded. 
• Preservation, use, and transportation of biological samples shall be carried out in such a 
manner as to also ensure their quality, integrity, availability and traceability. 
• Genetic data shall be transmitted electronically by certified electronic mail after encrypting 
and digitally signing the information to be transmitted. Web application-based 
communication channels may be used if they rely on secure communication protocols and 
they can guarantee the digital identity of the server providing the service as well as of the 
client station from which the data are accessed by means of digital certificates issued by a 
certification authority in pursuance of the law. 
• Electronically processed genetic data may be accessed provided that authentication systems 
are based on tokens/devices. 
• Genetic data and biological samples contained in lists, registers and/or databases shall be 
processed with encryption techniques and/or by means of identification codes and/or any other 
techniques that can make them temporarily unintelligible also to the persons authorised to 
access them. 
• In order to minimise the risks of accidental disclosure and/or unlawful/unauthorised access, 
subjects’ identities will be disclosed only when strictly necessary (e.g. to prevent a physical 
prejudice).  
• Genetic and medical data will be processed separately from any other personal data that can 
identify the subjects directly. 


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• The ICF will detail the possible findings regarding genetic data, also with regard to 
unexpected findings that might be disclosed as result of the test / elaboration of genetic data. 
• The ICF will detail whether the data subject is allowed to limit the scope of communication 
of genetic data and the transfer of biological samples, including their possible use for 
additional purposes. 
• The ICF will detail the retention period of genetic data and biological samples (if different 
from the general retention period of other data processed in the context of the study). 
5.11.9 Transfer of subjects’ data outside the European Union  
The study performance entails transferring subjects’ personal data (coded data) outside the EU. To 
this extent, the Sponsor, the Site, the Principal Investigator, the Central Laboratories, the CRO 
undertake to export such data in compliance with adequate safeguards/legal basis as required by the 
Regulation 679/2016 including the Commission Decisions, the Standard Contract Clauses, the 
Privacy Shield, subjects’ specific consent. Examples of non EU countries/entities including but not 
limited to USA . The complete list will be available upon request.  
5.11.10 Exercise of subjects’ data privacy rights  
Each study subject has the right to contact the Sponsor, the Clinical Research Site, the Principal 
Investigator, the Central Laboratories , the CRO to exercise the rights afforded to the subject by the 
law, including the afforded ones under articles 15 to 22 of Regulation (EU) 2016/679, namely: 
knowing whether or not any data referring to him/her is being processed in the context of the study; 
access his/hers data; verify the data’s content, origin, exactness, location (including, where applicable, 
the non EU countries where the data might be); obtain a copy of the data including their transmission 
to another entity indicated by the subject; ask that the data are supplemented, updated, amended; in 
the circumstances set forth by the law, ask that the processing of data is restricted, that data are 
anonymised or frozen; oppose to the processing of his/hers data for legitimate reasons. Each subject 
has the right to lodge a complaint with him/her local supervisory authority and/or to notify to the Data 
Protection Officer any use of him/her personal data the subject regards as inappropriate. 
Each study subject is free to withdraw at any time from the study. In such case, each study subject 
may ask the Sponsor, the Site, the Principal Investigator, the Central Laboratories, the CRO to 
destroy/delete his/hers personal data (including biological (see § 8.2.4) and unless they have been 
permanently anonymised), thus preventing any further processing or analysis of his/hers data. 
However, data and results of tests that may have been used to determine the results of the study shall 
not be deleted, to avoid altering or impairing altogether the results of the study.  
Specific rights in relation to the processing of genetic data applies. Please refer to § 5.11.8.   


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If the Site, the Principal Investigator, the Central Laboratories , the CRO receive a request for data 
privacy rights exercise, the concerned recipient shall immediately inform the Sponsor DPO by email 
at dpo@menarini.com or dpo.germany@berlin-chemie.de . 
The request shall be fulfilled within the term set forth by the applicable privacy laws (normally 30 
days). The Sponsor, the Site, the Principal Investigator, the Central Laboratories, the CRO shall 
implement adequate organisational measures to reply to subjects within the above mentioned 
deadline. 
5.11.11 Future Research  
Upon CA/EC approvals received, with subjects' optional and additional consent, the Sponsor and/or 
the Site may use the data collected during the course of the study for further medical and scientific 
research purposes. These may include, for example: retrospective clinical studies; clinical studies 
pertaining to the subjects’ pathology/medical condition(s) or similar conditions; studies which 
compare the data of this study with those from other sources to identify the factors involved in a 
disease; registration of new drugs. 
In the context of these additional research activities, subjects’ data will be processed, pseudonymised 
and transferred abroad and may be shared with future research partners –in most cases this will 
prevent subject identification; however, in the unlikely event subjects’ full identity really needs to be 
disclosed, the same precautions and safeguards as those described in this protocol will be 
implemented. 
 


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6. BACKGROUND INFORMATION 
 
Disease and Study Rationale 
Breast cancer has the highest incidence among all cancers worldwide, with 1.7 million new cases 
recorded in 2012, accounting for 12% of all new cancer diagnoses. It is also the fifth highest cause of 
cancer-related death, with a mortality of 23.1/100.000 (1, 2). Advanced breast cancer (ABC) 
comprises both locally advanced and metastatic breast cancer (MBC) (3). Although treatable, MBC 
remains an incurable disease with a 5-year survival of only 25% (4, 5, and 6). Only recent data seem 
to indicate an improvement in median overall survival (OS) (7). 
Breast cancer is a heterogeneous disease family comprising a number of subtypes. Biologically it is 
classified based on the expression of the oestrogen receptor (ER), progesterone receptor (PgR) and 
human epidermal growth factor receptor-2 (HER-2). Thus, it is possible to identify 5 distinct 
molecular subtypes: luminal A, luminal B (HER2-negative), luminal B (HER2-positive), 
HER2-positive and triple negative subtypes; each subtypes are linked to specific therapeutic 
indications. 
HER2-positive (HER2+) breast cancer represents 15% to 30% of all breast cancers and it is associated 
with aggressive behaviour and poor prognosis (8). Even if the use of the anti-HER2 antibody 
trastuzumab has led to important clinical benefits in this setting, 50% to 74% of subjects with 
metastatic disease do not respond to treatment (9, 10) and approximately 75% progress within a year 
(10). Beyond trastuzumab, new therapeutic options (trastuzumab emtansine [trastuzumab-DM1, 
T-DM1], lapatinib, pertuzumab) have provided important clinical benefits in terms of OS, but disease 
progression on HER2-directed therapy is experienced by most subjects, thus new strategies are 
needed. 
Among the subtypes, hormone receptor (HR)-positive tumours are the most common, as at least 80% 
of breast cancer express ER and PgR. Anti-estrogen therapies are a mainstay for this setting of 
subjects, antagonizing estrogen ligand binding to ER (tamoxifen and other selective ER-modulators), 
inhibiting dimerisation and down-regulating ER (fulvestrant and other selective estrogen receptor 
downregulators) or blocking oestrogen production (aromatase inhibitors; letrozole, anastrozole, 
exemestane). Unfortunately, not all of these tumours are truly sensitive to manipulation of the ER 
pathway, with approximately 20% of HR-positive MBC proving refractory to first-line endocrine 
therapy. Thus, the emergence of resistance to endocrine therapy is inevitable with advanced breast 
cancer as a clinical benefit rate declines from approximately 70% for first-line fulvestrant or 
aromatase inhibitors to around 30% for second or greater lines of therapy (11). 


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The study rationale comes from the evidence that a large body of experimental and clinical data 
suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most 
frequently mutated pathway in breast cancer, plays a major role in promoting resistance both in 
HER2-positive and in HR-positive breast cancer (12); its frequency has been identified in 
approximately 35% of HR-positive and approximately 25% to 30% of HER2 positive breast cancers 
(13, 14). 
Similar to other PI3K inhibitors given in combination with trastuzumab (15), the inhibition of PI3K 
signalling pathway in subjects with PIK3CA mutated HER2 positive locally recurrent unresectable 
(advanced) or metastatic (a/m) breast cancer progressed to anti- HER2 based therapy will be 
evaluated in tumor biopsy (target tissue - when available) as well as in normal tissues (platelet-rich 
plasma [PRP] and hair follicle) in the present study to: 
• Confirm the dose-dependent target inhibition observed in subjects with advanced solid 
tumours after administration of MEN1611 single-agent.  
• Characterise target engagement following the administration of MEN1611 twice daily (BID) 
schedule and after repeat dose administration.  
• Generate additional evidences on the relationship between drug exposure, target engagement, 
tumour effects and PFS/OS in order to identify the optimal biomarker and normal tissue to be 
used as a surrogate for clinical response.  
Although tumour biopsies are considered to be the gold standard for assessing molecular changes in 
tissue, the assessment of target modulation in normal tissue (PRP and hair follicle) reduce the risks 
associated with repeated tumour biopsies and enable serial determinations of drug effects, thus 
minimizing the impact of inter- and intra-subject variability on such results. However, such surrogate 
methods may be hampered by differences in e.g. drug penetration (and concentrations), gene 
expression and signal transduction pathway regulation among different tissues. Therefore it is 
important to assess multiple pharmacodynamics (PD) biomarkers in both PRP and hair follicle in 
order to comprehensively evaluate the overall pharmacological effects of the treatment, avoiding the 
risk of over-interpreting results from a single PD marker evaluation (16). 
PRP [17, 18, 19 and 20] and hair follicle [21] offer a good normal tissue matrix in which to measure 
pharmacodynamic biomarkers of the PI3K/AKT/mTOR signalling pathway. 
 
PI3K Inhibitor in Cancer Therapy 
The PI3K and mammalian target of rapamycin (PI3K-mTOR) pathway regulates cell growth, 
proliferation and metabolism and is a deregulated signalling pathway in human cancer (22). Genetic 
aberrations in this pathway, such as mutation or amplification of phosphatidylinositol 3-kinase, 


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catalytic, alpha polypeptide gene (PIK3CA), which encodes the p110α isoform of PI3K or 
inactivating mutations of phosphatase and tensin homologue (PTEN), occur in most epithelial 
tumour, leading to constitutive hyperactivation of downstream effector kinases such as v-akt murine 
thymoma viral oncogene homologue (Akt, protein kinase B) and mTOR. The high frequency of PI3K 
pathway alterations in HER2-positive breast cancer, combined with its role in resistance to 
trastuzumab and preclinical evidence that the PI3K inhibition restores sensitivity to trastuzumab with 
a higher anti-tumour activity than single agent, supports the rationale for clinical evaluation of 
combined targeting of PI3K and HER2 in subjects with HER2-positive breast cancer. On the other 
hand, activating PIK3CA mutations are often observed in HR-positive breast cancer (about 40% 
activating mutations detected) (14) and have been associated with disease progression and endocrine 
therapy resistance; targeting PI3K is therefore a potential therapeutic strategy. Particularly, 
identification of subjects with PIK3CA mutations who derive benefit from PI3K targeted therapy 
could help to guide treatment decisions (23). These data are supported by literature evidences, as 
PIK3CA mutated breast cancer has a better response to treatment than PIK3CA wild type tumours 
(24, 25). 
MEN1611 is a potent, selective Class I PI3K inhibitor with a novel structure which exhibited a strong 
inhibitory activity especially against PI3Kα. In preclinical models, MEN1611 was effective in a broad 
range of tumour types and showed efficacy in HER2-positive breast cancer xenograft models, 
harbouring PIK3CA mutations. The activity of MEN1611, at a clinically relevant dose of 6.5 mg/Kg, 
in combination with trastuzumab induced even complete responses in the treated mice.  
In the Phase I first-in-human (FIH) study, 38 subjects out of 39 enrolled have been treated with 
MEN1611 at different dose strengths. MEN1611 was well tolerated and the majority of the study 
treatment-related adverse events (AEs) were grade 1 or 2, reversible and in line with the class of the 
drug (gastrointestinal, hyperglycaemia and fatigue). The maximum tolerated dose (MTD) was 
determined to be 48 mg BID. At this dose, the drug exposure was consistent with the preclinical 
models.  
Several clinical studies showed a synergistic anti-tumour activity in breast cancers treated with the 
dual inhibition: PI3K inhibitors with fulvestrant in HR-positive disease and PI3K inhibitors with 
trastuzumab in HER2-positive setting (15, 24, 25, 26 and 27). 
The preclinical and clinical evidences, as well as the literature data regarding other PI3K inhibitors, 
support the rationale to develop MEN1611 in combination with trastuzumab and with trastuzumab 
plus fulvestrant for the treatment of PIK3CA mutated HER2-positive locally recurrent, unresectable 
advanced or metastatic (a/m) breast cancer subjects pre-treated with at least 2 lines of anti-HER2 
based therapy. Activating PIK3CA mutations (encoding the p110α isoform of PI3K) are often 


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observed in hormone receptor-positive breast cancer and have been associated with disease 
progression and endocrine therapy resistance. Preclinical and early clinical investigations showed that 
resistance can arise through enhanced oestrogen receptor pathway signalling, such as through ESR1 
mutations. Combining PI3K inhibition with the oestrogen receptor antagonist fulvestrant can prevent 
oestrogen receptor activation, resulting in synergistic antitumour activity. Thus, dual blockade of 
PI3K and oestrogen receptor pathways could restore treatment sensitivity and inhibit growth of 
endocrine therapy-resistant tumours (24). At the same, resistance to HER2-targeted therapy might 
occur as a result of aberrant activation of signaling pathways downstream of the receptor. Because 
HER2 mediates signal transduction through the PI3K/Akt/mTOR pathway, inhibition of components 
of the PI3K/Akt/mTOR pathway might be a reasonable way to overcome resistance and restore 
sensitivity to HER2-targeted therapy. Indeed, preclinical and neoadjuvant trial data suggest that 
PIK3CA alterations confer resistance to HER2-targeted therapy and are associated with lower 
pathological complete response (pCR) rate in HER2-positive breast cancer. (28). 
The development plan of MEN1611 in combination with trastuzumab and with trastuzumab plus 
fulvestrant will start with this Phase Ib study (MEN1611-01) with the main purpose to identify the 
MTD and select the recommended Phase 2 dose (RP2D) of MEN1611. After a classic 3 + 3 
Dose-escalation Phase, in the Cohort-expansion Phase the following selected cohorts of subjects will 
be considered: MEN1611 with trastuzumab and fulvestrant in HER2-positive, HR-positive 
postmenopausal women and MEN1611 with trastuzumab in the HER2-positive,  HR-negative men 
and women, and  HR-positive men and premenopausal women.. Indeed, safety, tolerability, 
pharmacokinetic (PK) and PD profiles as well as preliminary clinical activity of those combinations 
will be assessed in niche populations. 
 
Investigational Medicinal Product: MEN1611 
6.3.1 Physical, Chemical and Pharmaceutical Properties and Formulation  
MEN1611 or 5-(7-Methylsulfonyl-2-morpholin-4-yl-6,7-dihydro 5-Hpyrrolo [2,3d]pyrimidin-4-yl) 
pyrimidin-2-ylamine methanesulfonate (molecular weight 473.53 g.mol-1) is a potent and selective 
Class I PI3K inhibitor with a novel structure. In particular, it has potent inhibitory activities against 
Class I PI3Kα. 
MEN1611 is yellow to greenish yellow powder or powder with lumps, stable in the solid state.  
The MEN1611 drug product is a hard hypromellose capsules for oral administration. One capsule 
contains 20.07 mg of MEN1611, which corresponds to 16 mg MEN1611 free base. The hard capsules 
are red opaque, capsules size 2. The capsule fill consists of MEN1611 and the following inactive 


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ingredients: lactose monohydrate, croscarmellose sodium, hypromellose and magnesium stearate. All 
excipients used in the formulation are compendial grade. 
Capsules of MEN1611 are packed in blisters consisting of a laminated aluminium foil sealed to a 
rigid aluminium foil, synonym: Al/Al blisters.  
6.3.2 
 
6.3.2.1
 
6.3.2.1.1
 


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6.3.2.1.2 
 
6.3.2.2  
 
6.3.2.3 
 
 
 


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6.3.3 Clinical Experience 
In the PA-001 EU dose-escalation FIH study, conducted by Chugai Pharmaceutical, MEN1611 was 
administered to subjects with advanced solid tumours for which there was no standard treatment 
available. The study was conducted in 4 clinical centres since August 2010 until December 2012.  
Of the 39 subjects enrolled in PA-001 EU study, 38 subjects were included in the safety population. 
MEN1611 was generally well tolerated and the majority of AEs and drug-related AEs were Grade 1 
or 2 in intensity and were reversible. The most common drug-related AEs (≥20% in total) were 
diarrhoea (34%), nausea (32%), fatigue (29%), stomatitis (26%) and decreased appetite (21%). The 
commonly reported Grade ≥3 AEs (≥10% in total) were anaemia (21%), diarrhoea (16%) and 
hyperglycaemia (13%). These events were restored when MEN1611 dose was decreased and/or 
discontinued. 
Dose-limiting toxicities (DLTs) were reported in 1/7 subjects in the 48 mg BID cohort (aspartate 
aminotransferase [AST] increased), 2/3 subjects in the 72 mg BID cohort (fatigue and 
encephalopathy) and 2/5 subjects in the 56 mg BID cohort (diarrhoea and mucosal inflammation). 
MEN1611 was well tolerated up to total daily doses of 96 mg when administrated once daily (QD) 
or BID. The MTD of MEN1611 was determined to be 48 mg BID. No deaths due to AEs were 
reported in this study. AEs leading to discontinuation of study treatment and AEs leading to 
modification of study treatment were reported in 8/38 and 13/38 subjects, respectively.  
At single and repeat dose, MEN1611 was absorbed and eliminated rapidly, with a low contribution 
of renal excretion on its total elimination. MEN1611 exposure (area under concentration-time curve 
[AUC] and maximum observed plasma concentration [Cmax]) was subject to large variability. In QD 
cohorts there was no clear evidence of accumulation, whereas a potential for MEN1611 accumulation 
was observed in the BID regimen. After QD administration, saturation of exposure was observed in 


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56 to 96 mg dose range at single dose and 32 to 96 mg dose range at repeat dose, suggesting that 
MEN1611 exhibits non-linear PK at these doses.  
Decreases in percent change from baseline for p-Akt in PRP, as a proof of mechanism for MEN1611, 
were observed for daily doses greater than 32 mg, after both single and repeat dose administration. 
Inhibition of p-Akt was also observed in 2 of the 3 tumour biopsy samples obtained in the study. 
No subjects had the best overall response of complete response (CR) or partial response (PR). Stable 
disease (SD) was reported in 8/33 (24.2%) subjects in total. Although there were no subjects who 
showed CR or PR, ≥ 30% decreases of standardised uptake value were reported in 4/23 subjects in 
the 2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging after 1 week of treatment 
(Cycle 1, Day 8). 
 
Risk Benefit Assessment 
Treatment options for HER2-positive, HR-positive metastatic breast cancer progressed over the 
standard treatment still represent a high medical need. 
Hyperactivation of the PI3K pathway represents the principal mechanism of resistance involved in 
the progression disease of HR-positive, as well as HER2-positive breast cancer (29). Therefore a 
number of PI3K inhibitors are under clinical investigation, including pan-PI3K inhibitors targeting 
all four isoforms of class I PI3K (e.g. buparlisib, pictilisib), as well as isoform-selective inhibitors, 
especially PI3Kα inhibitor, such as taselisib and alpelisib (30, 31). Considering the potential high 
level of toxicity of pan-PI3K inhibitors, some of them were discontinued in spite of the evidence of 
clinical activity both in monotherapy and in combination (i.e., buparlisib) (24). As far as concerns 
this aspect, the isoform selective inhibitors like MEN1611 showed a better safety profile with a good 
risk-benefit ratio in the FIH study conducted by Chugai Pharmaceutical. 
MEN1611 is a potent, selective class I PI3K inhibitor with a strong inhibitory activity against PI3Kα 
which has shown a cytotoxic activity in vitro and in vivo models as single agent as in combination. 
Moreover, in the FIH conducted previously by Chugai Pharmaceutical, MEN1611 has shown a good 
safety profile, in line with the class of agent, furthermore an encouraging anti-tumor activity, resulting 
in disease stabilization in 24% of treated subjects, has been observed (PA-001 EU Clinical Study 
Report, data on file).  
Therefore, given the lack of standard therapeutic options for the selected subject population and the 
pharmacological properties and acceptable toxicological profile shown in preclinical and clinical 
studies, the risk-benefit assessment is considered favourable in the context of the clinical study. 
Considering the above, the intent is exploring the safety and activity of MEN1611 plus trastuzumab 
not only in HER2-positive/HR-negative breast cancer, but also in hormone-sensitive disease adding 


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fulvestrant to the double combination. If this study demonstrates efficacy signal, MEN1611 could 
offer a new therapeutic approach in the treatment of pre-treated locally recurrent unresectable a/m 
HER2-positive/HR-positive or negative breast cancer in combination with trastuzumab ± fulvestrant.  
The potential for drug-drug interaction (DDI) between MEN1611 and trastuzumab is relatively low 
considering that: (i) there is no evidence in the literature of PK interactions between trastuzumab and 
other small molecules; (ii) considering the pathways involved in the elimination of a small molecule 
(e.g. renal and biliary excretion, CYP450-mediated metabolism) and a monoclonal antibody (e.g. 
renal metabolism, immunogenicity, Fc receptors, target mediated clearance), most of the possible 
DDI mechanisms can be ruled out in the case of MEN1611 and trastuzumab; (iii) the PK profile of 
buparlisib (PI3K inhibitor) is not influenced by the concomitant administration with trastuzumab (15). 
 
 
 
 
 
 
 
 
 
 
In this study, MEN1611 treatment will be continued until objective disease progression is 
documented or another criterion for discontinuation (e.g., toxicity, withdrawal of consent) is met for 
subjects affected by metastatic breast cancer.  
To mitigate the risk of the administration of the study treatment and to guarantee the subjects’ safety 
during the study participation, the following measures have been applied in accordance with 
European Medicines Agency (EMA) guidelines (32): 
1. The dose-escalation will follow the traditional 3 + 3 study design; we decided to consider the 
maximum dose of 48 mg BID according to the data in the Investigator’s Brochure (IB), being 
the MTD in the FIH study. The 48 mg dose given BID offers a good safety profile, as 
MEN1611 was well tolerated and successfully inhibited the PI3K pathway. Considering the 
combination therapy, the MEN1611 starting dose selected for the dose escalation is 1/3 of the 
MTD, which is still able to actively inhibit the PI3K pathway. 


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2. Although MEN1611 did not show any mood disorder in the FIH study, we exclude subjects 
having any serious and/or unstable pre-existing psychiatric or neurologic illness or other 
conditions that could interfere with subject's safety, considering the toxicity profile of the class 
of drug (i.e., buparlisib). 
3. As far as treatment with trastuzumab is concerned, for the first administration, subjects will 
be monitored for at least 6 hours after the start of the first infusion and for 2 hours after 
subsequent infusions. In order to mitigate the potential risk of severe and fast progressing 
infusion reactions premedication is recommended, according to local practice. MEN1611 as 
other PI3K inhibitors are reported to cause gastro-intestinal AEs and hyperglycaemia; for this 
reason, a strict monitoring of safety laboratory test including blood sugar levels as well as 
recording any AEs will be done at each visit and appropriate supportive care will be 
immediately started; moreover, being well described in the FIH Chugai Pharmaceutical study 
that the occurrence of gastrointestinal side effects, as well as hyperglycaemia are common and 
could be severe, we have clearly stated in the exclusion criteria that National Cancer Institute 
Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) ≥grade 
2 diarrhoea, which is not resolved in the week prior to the start of treatment will be considered 
an exclusion criteria; similarly, subjects with uncontrolled diabetes mellitus (glycated 
haemoglobin [HbA1c] > 7%) and fasting plasma glucose (FPG) > 126 mg/dL will not be 
included in the study. 
Risk Benefit Assessment for COVID-19 pandemic 
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel 
coronavirus SARS-CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This 
new virus has rapidly spread across the globe causing the World Health Organization (WHO) to 
declare a pandemic situation on March 12, 2020. In response to the pandemic, the health authorities 
have issued recommendations on the further conduct of clinical studies. Accordingly, risk 
assessments of involvement in the trial with added challenges due to COVID-19 and mitigation 
measures need to be taken into consideration in all clinical studies to protect subjects, site staff and 
the society as a whole. 
 
This is a phase I clinical trial for heavily pre-treated subjects with locally advanced or metastatic 
breast cancer with few tolerable and efficacious therapeutic available options as per standard of care. 
The eligibility of subjects to the study will be evaluated by the treating physician/PI/sub-investigator 


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after individual assessment that the clinical benefit of the investigational products will outweigh the 
risk of contracting the SARS-CoV-2 infection without compromising the safety of the subjects. 
  
Measures to mitigate the additional risks caused by COVID-19 are: 
• Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered. 
• Subjects will be encouraged to follow strictly local mitigation recommendations when 
ambulatory (e.g., social distancing, use of mask, etc.). 
• Access to Clinical site will be as per local COVID-19 control measures. 
• Since the implementation of this protocol version 4, subjects on 3-weekly trastuzumb 
administration schedule will visit the hospital less often for undergoing treatment 
administration and procedures, and laboratory assessment. Particularly, visits will be 
performed on a 3-weekly basis (instead of weekly) starting from Cycle 5 Day 1 (after 12 
weeks of treatment) without affecting the subject’s safety considering that the most common 
and clinically relevant toxicities have been observed during the first 8 weeks of treatment. 
• For patients on 3-weekly trastuzumb administration schedule, weekly safety follow-up for 
AE and concomitant medications after Cycle 5 Day 1 will be done by phone to decrease the 
subjects’ visits. 
• Based on the local circumstances, to be reassessed on an ongoing basis, additional measures 
will be considered for implementation including: 
o Interruption or slowing down of recruitment of new trial participants;  
o Postponement of activation of sites that have not yet been initiated; 
o Transfer of trial participants to investigational sites away from risk zones, or closer 
to their home; 
o IMP re-distribution among sites, in case of shortage of study drug; 
o Increase of IMP kits dispensation during the site visits to cover longer periods of 
time and/or distribution of IMP to study participant’s home; 
o Administration of trastuzumab to be performed at local outpatient facilities closer to 
participants’ home, in case the trial participants cannot reach the site; 
o Safety laboratory tests to be performed at local laboratory or participant’s home, in 
case the trial participants cannot reach the site; 
o Remote consent could be collected (when applicable as per site policy). 
 


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7. STUDY OBJECTIVES  
 
Primary Objectives 
• To determine the MTD and RP2D of MEN1611 when administered orally in combination 
with trastuzumab ± fulvestrant to adult subjects with PIK3CA mutated HER2-positive breast 
cancer, pre-treated with at least 2 anti-HER2 based therapy. 
 
Secondary Objectives 
• To assess the safety and tolerability of MEN1611 in combination with trastuzumab ± 
fulvestrant. 
• To assess the preliminary anti-tumour activity and clinical efficacy of MEN1611 in 
combination with trastuzumab ± fulvestrant.  
• To assess the PK profile of MEN1611 when given in combination with trastuzumab ± 
fulvestrant. 
 
 


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8. INVESTIGATIONAL PLAN 
 
Overall Study Design and Plan Description 
This study is designed as an open-label, multicentre, Dose-escalation and Cohort-expansion, Phase Ib 
combination study to be conducted in approximately 50 European, Russian and US sites.  
Subjects with HER2-positive a/m breast cancer harbouring PIK3CA mutation and pre-treated with at 
least two lines of anti-HER2 based therapy will be enrolled. 
The study design is in agreement with the current regulatory EMA guidelines regarding the evaluation 
of anticancer medicinal products in man [EMA, Guideline on evaluation of anticancer medicinal 
products in man, Rev. 4 - December 2012; EMA/CHMP/205/95 under revision (Rev.5)]. 
The study is aimed to determine the MTD and RP2D of MEN1611 when administered in combination 
with trastuzumab ± fulvestrant to aforementioned subjects according with HR status. 
The study will consist of 2 sequential steps. The overall study design is shown in Section 2.1. At the 
time of the implementation of this Protocol Version 4.0, Step 1 has been completed. Step 2 study 
procedures for subjects on a 3-weekly trastuzumab administration schedule are tabulated in 
Sections 2.2, 2.3, 2.4 and 2.5 and described in Section 8.5.2. For subjects who started on a weekly 
trastuzumab administration schedule (patients already included in the study at the time this Protocol 
version 4.0 is in force), Step 2 study procedures are described in APPENDIX I: Study Procedures 
ONLY for subjects on weekly trastuzumab administration schedule. 
Step 1 (Dose-escalation Phase):  
A 3-cohort, ascending-doses’ (16 mg, 32 mg and 48 mg, BID) design identified the MTD and the 
RP2D of MEN1611 in combination with trastuzumab ± fulvestrant with 
MEN1611 to be  given in combination with weekly intravenous infusion of trastuzumab ± 4-week 
intramuscular (IM) injection of fulvestrant until objective disease progression is documented or 
another criterion for discontinuation is met. 
The number of subjects per cohort was assigned according to a 3 + 3 classical design, e.g. a minimum 
of 3 subjects in each dose cohort and if 1 of the first 3 subjects experiences a dose limiting toxicity 
(DLT), 3 additional subjects were to be assigned to the same dose level. 
The MTD is defined as the highest dose level at which no more than 1 of 6 subjects experience a DLT 
during the DLT assessment window (28 days). 
RP2D is defined as MTD or the maximum dose judged to be tolerable by the SRC. 
Step 2 (Cohort-expansion Phase): 


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The RP2D will be confirmed in additional male and female subjects with PIK3CA mutated/HER2+ 
a/m breast cancer, in order to achieve a total of 30 subjects in each of the following treatment cohorts 
exposed to the MTD: 
• HR-negative men and women, and HR-positive men and premenopausal women will be 
enrolled to receive MEN1611 + trastuzumab. 
• HR-positive postmenopausal women will be enrolled to receive MEN1611 + trastuzumab + 
fulvestrant. 
Note: Hormonal treatment such as GnRH analogs as per clinical local practice is allowed in 
HR-positive premenopausal women and male subjects assigned to receive MEN1611 + trastuzumab. 
Step 2 will explore the preliminary anti-tumour activity of MEN1611 combined with trastuzumab ± 
fulvestrant with further assessment of their safety and tolerability. 
The overall study duration will depend on the completion of the escalating dose levels/cohorts, the 
number of subjects to be treated per each dose-cohort, the completion of the expansion cohort up to 
a total of 30 subjects in each of two treatment cohorts exposed to the MTD and the duration of 
subject’s response. All subjects pre-screened for the PIK3CA mutation will undergo a maximum 4-
week Screening Period. If the complete assessment of the eligibility criteria is available within 3 days 
from the end of the Screening Period, the subject’s eligibility must be confirmed by the Medical 
Monitor. Screen failures can be re-screened upon Medical Monitor’s approval. 
. Individual study duration will depend on the duration of the study treatment which will continue up 
to disease progression or study discontinuation for other reasons. The End of Study Visit will be 
performed 4 weeks (± 7 days) after the last dose of MEN1611 or at the time of Study Withdrawal. 
Unscheduled assessments showing disease progression and leading to subject’s withdrawal can 
replace the End of Study Visit provided that all assessment/procedures scheduled for this visit are 
completed. After the End of Study Visit, all subjects evaluable for efficacy will be followed for 
survival status according to local practice (a visit or a telephone call) every 12 weeks ± 7 days up to 
the End of Study. 
After permanent withdrawal of the study treatment, subjects will be allocated to any other standard 
treatment as per the Investigator judgement.  
The study will end with the End of Study Visit of the last subject who discontinues the study treatment 
). For safety monitoring, all serious adverse events (SAEs) with a suspected causal relationship to the 
study treatment that occur after End of Study must be recorded and notified to the Sponsor as reported 
in section 8.6.2. 


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. 
 
Selection of Study Population 
Subjects with HER2 positive locally recurrent unresectable a/m breast cancer who: 
• are on an ongoing second line of treatment or 
• have received at least 2 lines of HER2-targeted therapies 
will be eligible for pre-screening.  
At the Pre-screening Visit, all subjects will sign the informed consent to perform mutational analysis 
for PIK3CA on the most recent archived FFPE tissue. For new patients to be included in the study at 
the time of this Protocol version 4.0 is in force, also a mutational analysis on plasma samples (for 
ctDNA sequencing, centrally analysed) will be performed after subject’s consent. However, inclusion 
in the study will be remain based on PIK3CA mutations detected in FFPE tissue only. 
Note: In case no archived tissue sample is available, a new biopsy of the primary tumour or a 
metastasis should only be obtained upon subject consent, and based on the investigators judgment 
that there is no additional safety risk to the subject’s safety. The samples will be centrally analysed 
using validated Cobas® PIK3CA Mutation Test. 
Subjects with HER2-positive a/m breast cancer harbouring PIK3CA mutation and progressed or 
pre-treated with at least 2 anti-HER2 based therapy will be enrolled. 
Eligibility of subjects to the study will be checked at Screening Visit and re-checked prior to the start 
of any treatment. 
Subjects will be included only if they meet all of the subject inclusion criteria (Section 8.2.1) and 
none of the exclusion criteria (Section 8.2.2), having provided written informed consent. 
8.2.1 Inclusion Criteria 
The following criteria must be met in order to be eligible to entry into the pre-screening: 
1. Ability to give written informed consent. 
2. Being male or female aged ≥ 18 years. 
3. Histologically confirmed invasive adenocarcinoma of the breast. 
4. Known HER2-positive breast cancer status defined as immunohistochemistry (IHC) 3+; if 
IHC is 2+ or 1+, fluorescence in situ hybridisation (FISH) confirmation is required, according 
to current ASCO/CAP (American Society of Clinical Oncology - College of American 
Pathologists) 2018 guidelines. 


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5. Known HR status (oestrogen receptor [ER] and/or progesterone receptor [PgR], with 
positivity defined as ≥1% immunoreactive tumour cell nuclei as per ASCO/CAP 2010 
guidelines on ER and PgR testing in breast cancer). 
6. Progression to at least one line of trastuzumab-based regime in the a/m setting and:  
• are on an ongoing second line of treatment or 
have received at least 2 lines of HER2-targeted therapies 
The following criteria must be met in order to be eligible to entry into the study: 
1. Having written informed consent before any study-related procedure. 
2.  Locally advanced or metastatic breast cancer harbouring PIK3CA mutation detected on 
the most recent archived FFPE tissue sample (or new tumour biopsy, if archived tumour 
tissue is not available) centrally analysed using validated Cobas® PIK3CA Mutation Test. 
3. Radiological documented evidence of progressive disease. 
4. Known menopausal status at the time of the initiation of the study, if applicable. 
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2. 
6. Life expectancy of ≥ 12 weeks. 
7. a) Having received at least 2 lines of anti-HER2 based regimens (e.g., pertuzumab, 
trastuzumab, 
lapatinib 
and 
trastuzumab-emtansine 
[T-DM1]) 
both 
in 
the 
advanced/metastatic (a/m) setting including at least 1 regimen containing trastuzumab. 
7. b) ONLY for France: Having received at least 2 lines of anti-HER2 based regimens both 
in the advanced/metastatic (a/m) setting including at least one regimen containing 
trastuzumab and one regimen containing trastuzumab-DMI  
8. Adequate cardiac function as defined by left ventricular ejection fraction of ≥ 50% 
measured by echocardiography or multi-gated acquisition (MUGA) scans. 
9. Adequate bone marrow function as defined by: absolute neutrophil count (ANC) of 
≥ 1.5 × 109/L, platelet count of ≥ 100.0 × 109/L and haemoglobin of ≥ 9 g/dL. 
10. Adequate liver function, as determined by total bilirubin within ULN ≤ 1.5 × ULN (≤ 
3 × ULN with direct bilirubin ≤ 1.5 × ULN, in case of subjects with coexisting known 
Gilbert’s disease) and AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases). 
11. Adequate renal function assessed by creatinine ≤ 1.5 × ULN or creatinine clearance ≥50 
mL/min (measured or calculated by Cockcroft-Gault formula). 
12. Not being pregnant or breastfeeding nor being a woman of childbearing potential 
(WOCBP) (see APPENDIX II: Contraceptive Guidance and Woman of Childbearing 
Potential). 


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Note: In case of being a WOCBP she must agree to use highly effective contraception 4 
weeks before the first dose of the study treatment, during the treatment period and for 
7 months following the last dose. Subjects should not breastfeed during the treatment 
period and at least for 7 months after the last dose of the study treatment.2 
13. Being male subjects, surgically sterile or  having agreed with true abstinence (must even 
refrain from heterosexual intercourse), and whose female partners are willing to agree with 
true abstinence or use barrier contraceptive measures during the entire study treatment 
period, and for 3 months after the last administration of the study drug. Males must agree 
to refrain from donating sperm during the entire study treatment period and for 3 months 
after the last administration of the study drug. 
Postmenopausal subjects with HR-positive breast cancer who ALSO meet the following criterion 
will be eligible for entry into the study: 
14. International normalised ratio (INR) ≤ 2. 
 
Note: Inclusion criteria 5, 9 to 11 and 14 (if applicable) will be re-evaluated prior to the start of any 
study treatment (Day 1 of Cycle 1). 
8.2.2 Exclusion Criteria 
Subjects will not be eligible to participate in the study if they meet ANY of the following exclusion 
criterion: 
1. Previous treatment with PI3K inhibitor, mTOR or AKT inhibitor. 
2. Hypersensitivity and/or contraindication to MEN1611, trastuzumab or to any component of 
the formulations. 
3. Known HER2 negative breast cancer in all biopsies performed throughout the disease,  
defined according to the ASCO/CAP  2018 guidelines (33). 
4. Inability to swallow oral medications. 
5. Untreated brain metastases, with the exception of subjects with previously treated brain 
metastases (including radiation and/or surgery) > 4 weeks earlier and only if clinically stable 
(as determined by the Investigator) and not receiving corticosteroids. 
6. History of clinically significant bowel disease including abdominal fistula, gastrointestinal 
perforation and diverticulitis. 
                                                 
2 The period of contraception and restriction on breast feeding has been included to be consistent 
with the recommendations in the trastuzumab summary of product characteristics (SmPC) 


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7. NCI CTCAE v4.03 ≥ grade 2 diarrhoea, which is not resolved in the week prior to the start 
of any study treatment (Day 1 of Cycle 1). 
8. History of significant, uncontrolled or active cardiovascular disease, specifically including, 
but not restricted to: 
• Myocardial infarction within 6 months prior to the first dose of any study treatment Day 
1 of Cycle 1, as applicable). 
• Unstable angina within 6 months prior to first dose of any study treatment (Day 1 of Cycle 
1). 
• Congestive heart failure (CHF) New York Heart Association Class III-IV. 
• Clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), 
as determined by the Investigator. 
• Long QT syndrome or other risk factors for “Torsades de Pointes” or increased QTc 
interval (QTc > 460 sec). 
• Ventricular arrhythmia.  
9. Cerebrovascular accident or transient ischaemic attack within 6 months prior to start of any 
study treatment (Day 1 of Cycle 1). 
10. Uncontrolled hypertension (defined as persistent blood pressure [BP] of ≥ 150/90 mmHg 
despite treatment, measured on at least 2 separate occasions). 
11. Known active or uncontrolled pulmonary dysfunction. 
12. Any serious and/or unstable pre-existing psychiatric or neurologic illness or other conditions 
that could interfere with subject’s safety. 
13. Uncontrolled diabetes mellitus (HbA1c > 7%) and FPG > 126 mg/dL. 
14. Known history of human immunodeficiency virus (HIV) infection or active infection with 
hepatitis C virus (HCV) or hepatitis B virus (HBV).  
15. Subjects diagnosed with another primary malignancy, except for: adequately treated non-
melanoma skin cancer or cervical cancer in situ; or subjects with another primary malignancy 
who are definitively relapse-free for at least 3 years since the diagnosis of the other primary 
malignancy. 
16. Concurrent chronic immunosuppressive treatment either with steroids or other 
immunosuppressive agents. 
17. Treatment with chemotherapy or immunotherapy (with the exception of anti-HER2 
antibodies) within 21 days before study drug treatment (Day 1 of Cycle 1). 


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18. Therapeutic radiotherapy or major surgery within 28 days before study drug treatment (Day 
1 of Cycle 1); or limited field palliative radiation therapy within 2 weeks before study drug 
treatment (Day 1 of Cycle 1).  
19. Any other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active 
or uncontrolled infection) that could cause unacceptable safety risks or compromise 
compliance with the protocol. 
 
 
 
 
21. Treatment with any other investigational agent within 28 days prior to starting the study drug 
treatment (Day 1 of Cycle 1) or within 5 half-lives of the investigational product, whichever 
is longer. 
22. Pregnant or breastfeeding women. 
23. Inability or unwilling to abide by the study protocol. 
Postmenopausal subjects with HR-positive breast cancer will not be eligible to participate in the study 
if they ALSO meet ANY of the following exclusion criteria: 
24. Hypersensitivity and/or contraindication to fulvestrant or to any component of the 
formulation. 
25. Any endocrine therapy for breast cancer (such as aromatase inhibitors or antioestrogens, with 
the exception of fulvestrant) within 28 days before the first administration of MEN1611 
(Day 1 of Cycle 1). 
26. Warfarin sodium therapy or any other Coumadin-derivative anticoagulant.  
27. Concurrent hormone replacement therapy. 
8.2.3 Withdrawal of Subjects from the Study or Discontinuation of the Study 
Treatment  
Participation in the study is strictly voluntary and subjects have the right to withdraw from the study 
at any time without explanation. This will not affect their rights for future medical care. Subjects may 
also be discontinued from the study treatment at the Investigator’s discretion or at specific Sponsor’s 
request at any time. 
8.2.3.1 Withdrawal from the Study 
The reasons for protocol-specified subject withdrawal are listed below: 


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• Informed consent withdrawn or the subject requests discontinuation from the study. 
• Any medical condition or personal circumstance (including pregnancy) which, in the opinion 
of the Investigator or the Sponsor, exposes the subject to risk by continuing in the study or 
does not allow the subject to adhere to the requirements of the protocol. 
• Disease progression during the study and where additional treatment medication will be 
necessary. 
8.2.3.2 Subject Withdrawal from the Study Medication 
Subjects will be withdrawn from the study if they experience: 
• Protocol 
violation 
(e.g., 
prohibited 
medication, 
poor 
compliance 
with 
study 
procedures/treatment). 
• AE with a possible, probable or certain drug-causality as per Investigator’s judgement of 
severity grade ≥ 3 CTCAE v4.03. 
• Disease progression. 
• DLT during 28 days after first MEN1611 administration.  
• Delay in scheduled treatment exceeding 21 days due to drug related toxicity. 
• Life-threatening related SAE. 
• Subject receives other treatment for breast cancer. 
• Occurrence of pregnancy. 
• Subject’s request. 
All subjects shall undergo the End of Study Visit at the time of study withdrawal or discontinuation 
of the study treatment. Unscheduled assessments showing disease progression and leading to 
subject’s withdrawal can replace the End of Study Visit provided that all assessment/procedures 
scheduled for this visit are completed.  
If a subject prematurely terminates the study as per subject’s request, data already collected will be 
used and analysed for the purpose of the study, as per local regulation. 
In case of withdrawal of consent, the subject may choose if samples/images which are already 
collected but not analysed yet, can be analysed or shall be destroyed. 
During the Dose-escalation Phase, subjects not evaluable for DLT will be replaced. 
8.2.4 End of Study 
The study will end with the End of Study Visit of the last subject who discontinues the study 
treatment. For safety monitoring, all SAEs with a suspected causal relationship to the study treatment 


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that occur after End of Study must be recorded and notified to the Sponsor as reported in section 
8.6.2. 
All biological samples excepting safety blood samples collected along the study will be stored for a 
maximum of 10 years from the date of the Last Subject Last Visit. After 10 years, the samples will be 
destroyed, or a new IEC/IRB approval and informed consent will be requested to keep the samples for 
an additional time period. 
 
Identity of the Investigational Products 
8.3.1 Description of Investigational Medicinal Products 
MEN1611: 
The drug product MEN1611 is a capsule for oral administration. One capsule contains 20.07 mg of 
MEN1611 which corresponds to 16 mg MEN1611 free-base and the following inactive ingredients: 
lactose monohydrate, croscarmellose sodium, hypromellose and magnesium stearate. All excipients 
used in the formulation are of compendial grade. The investigational medicinal product (IMP) is 
packed in Al/Al blisters. The blisters will be packed as subject kits according to the study design.  
Doses of 32 mg and 48 mg of MEN1611 free-base will be reached by administration of 2 or 
3 capsules at the same time. 
The storage recommendations for the MEN1611 capsules “Do not store above 25°C" (for EU sites 
and RU) and “Do not store above 77°F” (for US sites) and “Store in the original package” are defined. 
 
 
 
MEN1611 will be given in combination with fixed dose of either trastuzumab or fulvestrant. 
Authorised market preparations of trastuzumab and fulvestrant will be used as combination test drug 
products. 
• 
Trastuzumab 
Trastuzumab 150 mg powder concentrate in solution form for infusion. 
• Dose: After reconstitution, 1 mL contains 21 mg trastuzumab. 
• Dosage form: Powder for concentrate for solution for infusion. 
• Route: Intravenous (IV) infusion. 
Fulvestrant 
Fulvestrant 250 mg solution for injection. 
• Dose: Pre-filled syringe contains 250 mg fulvestrant in 5 mL solution. 
• Dosage form: Solution for injection. 


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• Route: Intramuscular (IM) injection. 
 
8.3.2 Packaging, labelling and storage 
MEN1611: 
The packaging and labelling of MEN1611 IMP is performed under the responsibility of the 
Department of Pharmaceutical Development of A. Menarini Research & Business Service GmbH 
(AMRBS), Glienicker Weg 125, 12489 Berlin, Germany. 
MEN1611 16 mg capsules will be packaged in aluminium-aluminium blisters (primary packaging) 
which are packaged in blister cards (secondary packaging) containing 3 blisters as described below: 
• Primary packaging: The drug product MEN1611 will be primary packaged in Al/Al blisters. 
• Secondary packaging: The IMP will be provided in treatment boxes (blister cards). The Al/Al 
blisters will be permanently fixed in blister cards containing 21 capsules each. 
Labelling: The IMP MEN1611 will be labelled in compliance with the current valid international and 
corresponding national requirements. Treatment box labels will have a peel-off section which has to 
be attached to the drug accountability form upon dispensing of the IMP at all visits during treatment 
Phase. The fixed section of the label will be a multilingual booklet reporting instructions on how to 
administer and store the MEN1611 IMP. 
Storage: At the study site, the MEN1611 IMP must be kept in a secure area inaccessible to 
unauthorised individuals. Furthermore, the Investigator will instruct the subject to keep MEN1611 
boxes according to the storage conditions given on the label.  
Distribution of MEN1611 treatment boxes will be under responsibility of AMRBS. 
Trastuzumab and Fulvestrant will be provided using authorized market preparation for EU and US 
sites. 
For EU and RU sites: 
Trastuzumab: 
Trastuzumab will be provided using the authorized EU market preparations of trastuzumab (vial 
containing trastuzumab 150 mg powder for concentrate for solution for infusion). 
The authorised product will not be modified except for re-packaging (secondary packaging and 
labelling). No additional substances or materials apart from secondary packaging will be added to the 
product. 
Trastuzumab will be re-labelled according to national/international requirements and distributed to 
study sites under the responsibility of the Department of Pharmaceutical Development of AMRBS.  


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The label will be a multilingual booklet reporting instructions on how to administer and store the 
medication. 
Trastuzumab powder for concentrate for solution for infusion has to be stored in the refrigerator (2°C 
to 8°C). For any additional information please refer to the clinical trial medication (CTM) manual in 
your files. 
Fulvestrant: 
Fulvestrant will be provided using the authorized EU market preparations of fulvestrant (pre-filled 
syringe containing 250 mg solution for injection). The authorised product will not be modified except 
for re-packaging (secondary packaging and labelling). No additional substances or materials apart 
from secondary packaging will be added to the product. 
Fulvestrant will be re-labelled according to national/international requirements and distributed to 
study sites under the responsibility of the Department of Pharmaceutical Development of AMRBS. 
The label will be a multilingual booklet reporting instructions on how to administer and store the 
medication. 
Fulvestrant 250 mg solution for injection has to be stored in the refrigerator (2°C to 8°C). For any 
additional information please refer to the CTM manual in your files. 
For US Sites: 
Trastuzumab and Fulvestrant for US study sites will be provided locally by the respective site’s 
pharmacy. 
8.3.3 Drug accountability  
MEN1611 (EU, RU and US) and Trastuzumab and Fulvestrant (EU and RU) 
Upon receipt of all study treatment, study site personnel or the designated pharmacist will open the 
shipment package, verify the contents as stated on the enclosed Delivery Note and confirm the receipt 
in the interactive web-response system (IWRS). 
The IWRS will be used to record the study treatment delivery to study sites and subjects, the inventory 
at the sites, including dates, quantities, expire dates and batch/serial number.  
The Investigator will be responsible for documenting the dispensing of the study treatment to the 
subject by entering the unique box number in the source documents and in the eCRF to allow drug 
accountability. 
In addition, the sites will maintain paper drug accountability forms to document the dispensed and 
administered study treatment per subject. The peel-off labels will be pasted onto these paper drug 
accountability forms.  


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Subjects will be instructed to return used or unused MEN1611 boxes at each visit to allow drug 
accountability for dispensed MEN1611. In the exceptional situation in which MEN1611 boxes 
retrieval is unattainable, the Investigator will be responsible for documenting drug accountability as 
per his/her knowledge.   
Trastuzumab and Fulvestrant (for US sites only) 
The Investigator will be responsible for documenting the dispensing of the study treatment to the 
subject by entering the batch number in the source documents and in the eCRF to allow drug 
accountability. In addition, the sites will maintain paper drug accountability forms to document the 
dispensed and administered study treatment per subject. 
Please refer to the CTM and/or IWRS manuals in your files for the instructions relevant to the drug 
accountability. 
8.3.4 Destruction of the Study Treatment 
Throughout the study and at the end of the study, all remaining study treatment will be reconciled 
under the responsibility of the Investigator at the study site. 
No later than the Site Close-out Visit, the used and unused MEN1611 IMP boxes shall be returned 
for destruction to the Department of Pharmaceutical Development of A.MRBS or to a local depot 
under Sponsor responsibility, if applicable, provided this is not in conflict with any national export 
legislation. 
In case local destruction is required due to national legislations a certificate of destruction, indicating 
the batch number and the box number needs to be provided. 
Trastuzumab and Fulvestrant (for EU and RU sites only) 
Used trastuzumab and fulvestrant boxes shall be destroyed locally while unused trastuzumab and 
fulvestrant boxes shall also be returned to the Department of Pharmaceutical Development of 
AMRBS or to a local depot under Sponsor responsibility, if applicable, provided this is not in conflict 
with any national export legislation. 
Any local destruction of the study treatment requires a certificate of destruction, indicating the batch 
number and the box number. 
Trastuzumab and Fulvestrant (for US sites only) 
Used Trastuzumab and Fulvestrant boxes shall be destroyed locally. 


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Treatments 
8.4.1 MEN1611 
Step 1 (Dose-escalation Phase): MEN1611 as oral capsules of 16 mg strength was orally 
administered BID for a continuous 28-days’ cycle. Three ascending dose cohorts of subjects will 
receive MEN1611  in increments as follows: 16 mg, 32 mg and 48 mg BID for a total daily dose of 
32 mg, 64 mg and 96 mg, respectively. 
In this Phase, MEN1611 was administered as below: 
• Cohort 1: MEN1611 16 mg capsules BID over 28-days’ cycle. 
• Cohort 2: MEN1611 32 mg (2 × 16 mg) capsules BID over 28-days’ cycle. 
• Cohort 3: MEN1611 48 mg (3 × 16 mg) BID over 28-days’ cycle. 
Step 2 (Cohort-expansion Phase): MEN1611 as oral capsules has to be orally administered BID at 
the RP2D as established in Step 1. 
 
 
 At Visit 2 and Visit 3 of Cycle 1, and at each following visits, MEN1611 
will be administered at site using the new boxes dispensed.  
8.4.2 Trastuzumab 
 For subjects already included in the study at the time of this Protocol version 4.0 is in force, 
trastuzumab has to continue to be administered according to a weekly schedule as described below. 
Premedication may be given according to local practice. 
• A loading IV dose of 4 mg/kg (over 90 minutes) on Day -7 will be administered (if considered 
appropriate by the Investigator based on the time elapsed from the last trastuzumab dose prior 
to study enrolment).  
If the initial loading dose is well tolerated, the subsequent doses can be administered as a 
30-minute infusion. Subjects will be monitored at the site for occurrence of AEs for at least 
6 hours after the start of the loading dose infusion. 
• Maintenance IV doses of trastuzumab 2 mg/kg will be administered (over 30 minutes if the 
previous infusion was well tolerated) weekly from Day 1 of Cycle 1. 
For new subjects to be included in the study at the time of this Protocol version 4.0 is in force, 
trastuzumab has to be administered according to a 3-weekly interval schedule as described below. 


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• IV doses of 6 mg/kg (over 30 minutes) will be administered every 3 weeks (Day 1 of each 
Cycle) 
Note: alternatively on Day 1 of Cycle 1, a loading IV dose of 8 mg/kg (over 90 minutes) could 
be administered, if considered appropriate by the investigator based on the time elapsed from 
the last trastuzumab dose prior to study enrolment. Subjects will be monitored at site for 
occurrence of AEs for at least 2 or 6 hours after start of the maintenance or loading dose 
infusion, respectively. 
The weekly administrations of trastuzumab are to be scheduled in order to maintain the dosing 
interval. In case of a missed dose, the usual maintenance dose should be administered as soon as 
possible. 
Each vial of trastuzumab has to be reconstituted with sterile water before the infusion with sodium 
chloride solution according to the instructions provided in the Summary of Products Characteristucs 
(SmPc).  
8.4.3 Fulvestrant 
In both Step 1 and Step 2, IM fulvestrant 500 mg will be administered only to HR-positive 
postmenopausal subjects every 4 weeks from Day 1 of Cycle 1; an additional dose will be 
administered on Day 15 of Cycle 1 to those subjects who were not under fulvestrant treatment prior 
Cycle 1 Day 1. 
Fulvestrant must be given according to the instructions provided in the SmPc.  
Note: The following warnings should be considered by the Investigators as per fulvestrant SmPc: 
Fulvestrant formulation contains 10% weight/volume ethanol (alcohol), i.e. up to 1000 mg per dose, 
equivalent to 20 mL beer or 8 mL wine per dose.  
Harmful for those suffering from alcoholism.  
To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as 
subjects with liver disease, or epilepsy. 
8.4.4 Sequence of Study Treatment Administration 
Based on PK profile of MEN1611, no potential DDI effects are expected, nevertheless, based on the 
time points for PK sample collection and logistics aspects, it is deemed suitable to recommend the 
following order of study treatment administration for cycles when all 3 study treatments are required 
to be administered: 
1. Trastuzumab 
2. MEN1611 


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3. Fulvestrant 
8.4.5 Treatment Compliance 
Subjects will be asked to complete a paper subject diary for the duration of their treatment with 
MEN1611 to record the study treatment compliance (see sec. 10.1.3). 
8.4.6 Management of Toxicities due to MEN1611 and Dosage Modification 
Cycle 1: 
Subjects should receive full doses of the study treatment unless a DLT is observed. No dose 
adjustment is permitted. In case of a DLT, the study treatment will be discontinued and the subject 
will be withdrawn from the study. 
Additional clinical and laboratory assessments will be performed 3 days after the observation of any 
of the following toxicities: 
• ANC <1.0 × 109/L. 
• Anaemia (haemoglobin < 8.0 g/dL). 
• Platelet count <75 × 109/L. 
• Non-haematological toxicity grade ≥2. 
• Grade ≥2 nausea, vomiting, skin rash, diarrhoea and hyperglycaemia despite adequate 
supportive measures. 
At the time of these additional clinical and laboratory assessments, subjects with no dose-limiting 
haematological and non-haematological toxicities will remain at the same dose and schedule.  
Cycle 2 and Subsequent Cycles: 
The study treatment will be administered only if all the following criteria for re-treatment are met: 
• ANC ≥1.0 x 109/L. 
• Platelet count ≥ 100.0 x 109/L. 
• No grade ≥2 non-haematological toxicity attributable to MEN1611, for nausea, vomiting, 
diarrhoea and hyperglycaemia despite adequate supportive measures. 
• Grade ≤2 general disorder (i.e., fatigue, asthenia) and asymptomatic grade ≤ 3 organ 
abnormalities which the Investigator judges not clinically relevant for continuing the study 
treatment. 
• Skin toxicity, if previously reported, must regress to grade ≤2. 


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Subjects experiencing any of the above toxicities must have an additional clinical and laboratory 
assessment every 3 days (a window of ± 1 day is allowed) until treatment may be resumed at the same 
full dose or at a reduced dose. 
No dose modification is allowed for trastuzumab or fulvestrant. Any MEN1611 dose reduction or 
interruption for toxicity will be permitted after the 28th day of the first treatment cycle, until the 
subject recovers from toxicity: 
• For grade 2 toxicity and/or <7 days delay in scheduled treatment, treatment will restart on 
the same full dose. 
• For grade 3 toxicity and/or 8 to 14 days’ delay in scheduled treatment, treatment will restart 
at a reduced dose (from 48 mg BID to 32 mg BID, and from 32 mg BID to 16 mg BDI). Up 
to two dose level reductions will be allowed. 
• For grade 4 toxicity and/or 15 to 21 days’ delay in treatment, the subject will be withdrawn 
from the study or may be treated with a reduced dose (the previous dose level as indicated 
above, according to Investigator’s clinical judgment). 
• If the delay in scheduled study treatment exceeds 21 days due to drug related toxicity, the 
subject will be withdrawn from the study. 
For specific toxicities such as hyperglycaemia, diarrhoea, and skin toxicity, Investigators may 
consider management recommendations in APPENDIX IV: Recommendations for Management of 
Toxicities related to MEN1611. 
Subjects meeting the re-treatment criteria may continue therapy until there is clear evidence of disease 
progression or intolerable toxicities or subject refusal, whichever occurs first. 
8.4.7 Prohibited and Concomitant Medications 
During the study subjects are not allowed to receive any chronic treatment with steroids or another 
immunosuppressive agent. 
Any chemotherapy, radiotherapy, immunotherapy (with the exception of anti-HER2 treatment), 
biologic treatment, and endocrine therapy in HR+ postmenopausal subjects is not allowed during the 
study and within 28 days of the first administration of any study treatment (Day ˗7 or Day 1 of 
Cycle 1, as applicable). 
 
 
 
 


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Within 30 days prior to Screening Visit no other investigational agent is allowed to be taken. 
Subjects with postmenopausal HR-positive breast cancer are not allowed to receive warfarin sodium 
therapy or any other Coumadin-derivative anticoagulant and concurrent hormone replacement therapy. 
Concomitant and prior (i.e., within 30 days before Screening) medications shall be carefully checked 
since the use of the above reported medications may represent an exclusion criterion making the subject 
ineligible to participate in the study. Furthermore, the regular and occasional use of any concomitant 
medication has to be recorded starting from Screening until the End of Study Visit. 
8.4.8 Dietary and Lifestyle Restrictions 
 
 
  
Alcohol consumption must be avoided from 48 hours before and during any study visit. Subjects should 
not consume more than 3 units per day during the off-site days during the study (1 unit = 200 mL beer 
or 100 mL wine or 25 mL distilled spirits). 
 
Study Procedures and Assessments 
8.5.1 Study Procedures for Step 1 and Step 2 ONLY for subjects who has 
started and continue on weekly trastuzumab administration schedule 
The study procedures for Step 1 and Step 2 ONLY for subjects who have been already included in the 
study at the time of this Protocol version 4.0 is in force  and shall continue to be  on weekly 
trastuzumab administration are described in the APPENDIX I: Study Procedures ONLY for subjects 
on weekly trastuzumab administration schedule. 
8.5.2 Study Procedures for subjects on 3-weekly trastuzumab administration 
schedule 
The study procedures for new subjects to be included in the study at the time of this Protocol version 4.0. 
is force (subjects on 3-weekly trastuzumab administration) are depicted in the study flow chart (see 


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Section 2.2) and summarised below by Pre-screening Period, Screening Period, and 21-day Treatment 
cycles. From Day 1 Cycle 1 up to Day 1 Cycle 5 (first 12 weeks of the study) weekly study visits are 
required, then visits are required every three weeks until the End of Study Visit. After the End of Study 
Visit, all subjects evaluable for efficacy will be followed for survival status according to local practice 
(a visit or a telephone call) every 12 weeks ± 7 days up to the end of study. 
Pre-screening Period: 
Subjects with HER2 positive a/m breast cancer will be eligible for pre-screening if they  have progressed 
to at least one line of trastuzumab based regimen in the a/m setting and : 
• are on an ongoing second line of treatment or 
• have received at least 2 lines of HER2-targeted therapies. 
At the Pre-screening Visit, all subjects will sign the informed consent to perform mutational analysis for 
PIK3CA and other relevant genes on the most recent archived FFPE tissue and in plasma samples 
(ctDNA sequencing, centrally analysed). Inclusion in the study will be done based on PIK3CA 
mutations detected in FFPE tissue only. 
Note: In case no archived tissue sample is available, a new biopsy of the primary tumour or a metastasis 
should only be obtained upon subject consent, and based on the investigators judgment that there is no 
additional risk to the subject’s safety. The samples will be centrally analysed using validated Cobas® 
PIK3CA Mutation Test. 
Screening Period (Day -27 to Day -1): 
During the 28 days prior to the first dose of MEN1611 and following provision of written informed 
consent, each subject will be screened for eligibility. 
The following procedures will be performed at Screening: 
• Check of inclusion/exclusion criteria. 
• Recording of demographic data. 
• Standard medical, surgical and medication history. 
• Smoking history and current status. 
• Verification of pre- or postmenopausal status (see APPENDIX II: Contraceptive Guidance 
and Woman of Childbearing Potential) in HR-positive women. 
• ECOG PS. 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature), height and weight. 
• Recording of AEs and concomitant medications. 


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• 12-lead ECG record. 
• Echocardiogram (ECHO) or MUGA scan. 
• Local tumour assessment using Response Evaluation Criteria in Solid Tumours (RECIST) 
(35) version 1.1 (v1.1) with computed tomography (CT) scan or Magnetic resonance imaging 
(MRI) for subjects with measurable disease.  
• Blood samples for haematology, coagulation and chemistry, HbA1c included. Blood sampling 
for anti-HIV antibodies, anti-hepatitis B core antigen (anti-HBcAg) antibodies, anti-hepatitis 
B surface antigen (anti-HbsAg) antibodies, HBV-DNA, HCV-ribonucleic acid (HCV-RNA). 
Note: In case the laboratory tests for anti-HIV antibodies, anti-HbcAg antibodies, anti-HbsAg 
antibodies, HBV-DNA and HCV-RNA have been performed within 3 months prior to 
Screening Period in the context of the standard subject’s management, these tests will not be 
repeated. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
• Optional new tumour biopsy to be performed upon subject’s consent and centrally analysed 
for PD.  
Note: Collection of tumour biopsy is recommended in order to confirm that the target 
inhibition is also occurring in the tumour. This should be particularly encouraged for tumours 
that can be readily biopsied. 
A screen failure is defined as follows: 
o A subject who does not meet the eligibility criteria required for study participation 
during the Screening Period. 
o A subject who no longer meets eligibility criteria at Day 1 of Cycle 1). 
o A subject whose time window between Screening and Visit 1 (i.e., Day 1 of Cycle 1, 
when applicable) is longer than 4 weeks. 
Note: If the complete assessment of the eligibility criteria is available within 3 days from the end of 
the Screening Period, the subject’s eligibility must be confirmed by the Medical Monitor. 
Screen failures can be re-screened upon Medical Monitor’s approval. 
A drop-out is defined as a subject who voluntarily withdraws from the study. 
Cycle 1: 
Visit 1 – start of MEN1611 treatment (Day 1): 


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(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Re-evaluation of inclusion/exclusion criteria and confirmation of subject’s eligibility prior to 
the start of the study treatment. 
• Tumour assessment using RECIST v1.1 with CT scan or MRI ONLY if older than 6 weeks.  
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• Blood sample for central analysis of tumour markers before the treatment: PIK3CA mutations 
in ctDNA and CTC enumeration. 
• 12-lead ECG record: pre-dose (same technique used at screening). 
• 12-lead ECG record: 2 hours post first daily MEN1611 dose administration (same technique 
used at screening). 
• Blood samples for haematology, coagulation and chemistry including HbA1c. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
 
 
 
 
 
  
 
  
• Dispensing of the subject diary for study treatment compliance.  
Note: Subjects will be asked to complete a subject diary for the duration of their treatment 
with MEN1611. 
• Recording of AEs and concomitant medications. 
• Cohort assignment for MEN1611 dose level (only for Step 1). 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 6 mg/kg as a 30-minute IV infusion. Alternatively 8 mg/kg over 90 
minutes (loading dose) will be administered, if considered appropriate by the 
Investigator based on the time elapsed from of the last trastuzumab dose received by 
the subject prior to study enrolment.  
Note: Subjects will be monitored at the site for occurrence of AE for at least 2 or 6 
hours after the start of the 6 mg/kg or 8 mg/kg trastuzumab infusion, respectively. 


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o Dispensing of MEN1611 and administration 
of the first assigned 
dose (16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects. 
Visit 2 (Day 8), Visit 3 (Day 15): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry. 
 
 
 
 
 
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects ONLY at 
Day 15 if the subject has started fulvestrant at Cycle 1 Day 1. 
Cycle 2 up to Cycle 4: 
Visit 1 (Day 1) (+ 3 days window): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
 
 
  
 
 
  
 
  
 
 


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• 12-lead ECG record (same technique used at screening) at Cycle 2 Day 1 (one pre-dose and 
one 2 hours post first daily MEN1611 dose administration) and at Cycle 3 Day 1 and Cycle 4 
Day 1  
• ECHO or MUGA scan (same technique used at screening) ONLY on Day 1 of Cycle 3 (-7 
days).  
• Blood samples for haematology, coagulation and chemistry including HbA1c. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
• Dispensing of the subject diary for study treatment compliance. 
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 6 mg/kg as a 30-minute IV infusion.  
Note: Subjects will be monitored at the site for occurrence of AE for at least 2 hours 
after the start of the trastuzumab infusion. 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
Visit 2 (Day 8), Visit 3 (Day 15): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• Blood sample for central analysis of tumour markers before the treatment: PIK3CA mutations 
in ctDNA, and CTC enumeration at Cycle 2 Day 8 and at Cycle 3 Day15. 
• Blood samples for haematology, coagulation and chemistry. 
 
 
 
 
  
• Tumour biopsy will be performed on Day 15 (Visit 3) of Cycle 3 (±7 Days) only in subjects 
who underwent the optional assessment at screening, and centrally analysed for PD. 
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 


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o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects ONLY on 
Day 8 of Cycle 2 and Day 15 of Cycle 3 (i.e. every 4 weeks from Day 1 of Cycle 1) 
• Tumour assessment using RECIST v1.1 with CT scan or MRI will be performed every 8 
weeks from the first MEN1611 administration (Day 1 Cycle 1). 
Cycle 5 onwards:  
Visit 1 (Day 1) (+ 3 days window) 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry including HbA1c. 
• Serum pregnancy test (if applicable). 
• Blood sample for central analysis of tumour markers before the treatment: PIK3CA mutations 
in ctDNA and CTC enumeration at Cycle 5 and every 2 Cycles.  
• Sample for urinalysis. 
• 12-lead ECG (same technique used at screening) on Day 1 of each Cycle. 
• ECHO or MUGA scan (same technique used at screening) won Day 1 of Cycle 6 (-7-day 
window) and on Day 1 of every third following cycle. 
• Dispensing of the subject diary for study treatment compliance. 
• Recording of AEs and concomitant medications to be repeated weekly by telephone call after 
Day 1 of Cycle 5. 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 6 mg/kg as a 30-minute IV infusion. 
Note: Subjects will be monitored at site for occurrence of AE for at least 2 hours after 
the start of the trastuzumab infusion. 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects on Day 1  of 
Cycle 5 and every 4 weeks onwards. 


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• Tumour assessment using RECIST v1.1 with CT scan or MRI will be performed every 8 
weeks from the first MEN1611 administration (Day 1 Cycle 1).  
End of Study Visit (4 weeks ± 7 days after last administered dose of MEN1611): 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature). 
• Smoking current status. 
• Tumour assessment using RECIST v1.1 will be performed if the last assessment is older than 
8 weeks. 
• ECOG PS. 
• ECHO or MUGA scan (same technique used at screening), if not performed within the 
previous 14 days. 
• Blood samples for haematology, coagulation and chemistry. 
• Sample for urinalysis. 
• Recording of AEs and concomitant medications. 
• Serum pregnancy test (if applicable). 
• Blood sample for central analysis of tumour markers: PIK3CA mutations in ctDNA and CTC 
enumeration. 
Note: All subjects shall undergo the End of Study Visit at the scheduled day (at time frame of 
± 7 days) or at the time of Study Withdrawal. Unscheduled assessment showing disease progression 
and leading to a subject’s withdrawal can replace the End of Study Visit provided that all 
assessment/procedures scheduled for this visit are completed. 
Survival Follow-up: 
After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status 
according to local practice (a visit or a telephone call) every 12 weeks (± 7 days) up to the End of 
Study. 
8.5.3 Sample Handling & Shipping Management  
In order to perform PK/PD, genetic, exploratory 
 
 
 and safety analyses a whole blood volume ranging between 15 and 71 mL, with a 
maximum amount of approximately 100 mL (only at Visit 1 of Cycle 1), need to be collected per visit. 


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Mutational status of genes such as (but not limited to) PIK3CA, PTEN, regulatory associated protein of 
mTOR, Akt3, Akt2, Akt1, tuberous sclerosis complex 2, PIK3R1, rapamycin-insensitive companion of 
mammalian target of rapamycin, serine/threonine kinase 11 and mTOR will be evaluated. 
Other than safety samples that will be locally analysed, biological samples will be processed at site and 
analysed centrally (for further details, please refer to the Laboratory Manual). 
8.5.4 Pharmacokinetics Procedure and Assessment 
The following PK parameters (Table 1) will be determined from the individual plasma concentration-
time curve for MEN1611 using non-compartmental methods with Phoenix™ WinNonlin® software, 
version 6.4 or higher (Pharsight Corp., Mountain View, California). 


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Table 1. 
Pharmacokinetic Parameters for MEN1161-01 Study 
Cmax 
Maximum observed plasma concentration. 
tmax 
Time to Cmax. 
Clast 
Last quantifiable plasma concentration value. 
tlast 
Time to Clast. 
Ctrough 
Pre-dose plasma concentration. 
ke 
Apparent terminal elimination rate constant, estimated by log-linear 
regression analysis on plasma concentrations visually assessed to be on 
the terminal log-linear phase. 
t½ 
The terminal plasma half-life, calculated according to the following 
equation:   
 
AUC(0-t) 
 
Area under the plasma concentration-time curves from time zero (pre-
dose) to the time of the last quantifiable concentration, calculated by 
means of the linear-log trapezoidal method. 
AUC(0-∞) 
Area under the plasma concentration-time curve from time zero to infinity, 
calculated according to the following equation:   
 
%AUCex 
The percentage of AUC(0-∞) obtained by extrapolation calculated as 
follows: 
 
CL/F 
Apparent systemic clearance, calculated according to the following 
equation:   
 
Vss/F 
Apparent volume of distribution at steady state, calculated according to 
the following equation:   
 
ek
t
693
.0
2
/
1
=
e
last
t)
(0
k
C
AUC
AUC
+
=
−
∞)
-
(0
100
*
(%)
)
(0
)
t
(0
)
(0
ex
AUC
AUC
AUC
AUC
∞
−
−
∞
−
−
=
 
AUC
Dose
F
CL
)
-
(0
/
∞
=
MRT
F
CL
F
Vss
*
/
/
=


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Vd/F 
Apparent volume of distribution based on the terminal phase, calculated 
according to the following equation: 
 
 
 
 
 
 
 
The calculation of the parameters listed above and others will depend upon the results of the drug 
concentration assay. 
 
AUC
*
k
Dose
F
V
e
d
)
-
(0
/
∞
=


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8.5.5 Pharmacodynamics Procedure and Assessment 
Assessment of MEN1611 biological activity when given in combination with trastuzumab ± 
fulvestrant will be performed in hair follicle, PRP and tumour biopsy. p-Akt, p-PRAS40 and other 
potential biomarkers related to the PI3K/Akt pathway (e.g. p-70S6K, and p-GSK3b) will be analysed. 
Details of the PD evaluation will be described in the Laboratory manual. 
Hair Follicle and Platelet Rich Plasma 
Hair follicles and blood sampling for PRP will be taken at the following timepoints: 
 
For subjects on weekly trastuzumab administration schedule 
• Day 1 and Day 22 of Cycle 1 (Visit 1 and Visit 4): Pre-dose (0 hours), 2, 6 and 12 hours 
after MEN1611 dose.  
• Day 8 and Day 15 of Cycle 1 (Visit 2 and Visit 3): Pre-dose and 2 hours after MEN1611 dose. 
• Day 1 and Day 15 of Cycle 2 (Visit 1 and Visit 3): Pre-dose. 
• Day 1 of Cycle 3 (Visit 1): Pre-dose. 
For subjects on 3-weekly trastuzumab administration schedule  
• Day 1 of Cycle 1 (Visit): Pre-dose (0 hours), 2, 6 and 12 hours after MEN1611 dose. A time 
window of -2 hours is allowed for the 12 hours timepoint.  
• Day 8 and Day 15 of Cycle 1 (Visit 2 and Visit 3): Pre-dose and 2 hours after MEN1611 dose. 
• Day 1 of Cycle 2 (Visit 1): Pre-dose, 2, 6 and 12 hours after MEN1611 dose. A time window 
of -2 hours is allowed for the 12 hours timepoint. 
• Day 8 of Cycle 2 (Visit 2): Pre-dose 
 
• Day 1 and Day 15 of Cycle 3 (Visit 1 and Visit 3): Pre-dose 
 
Note: Hair follicles should preferably be collected from the eyebrow, however scalp is acceptable 
(please refer to the Laboratory manual).  
Hair follicle samples will be centrally analysed for the assessment of p-PRAS40. 
PRP samples will be centrally analysed for the assessment of p-Akt, and other potential biomarkers 
related to the PI3K/Akt pathway. 
Tumour Biopsy (optional dependent on subject consent)  
Optional tumour biopsy will be performed upon subject’s consent before the first daily dose of 
MEN1611 (Screening Period); a second biopsy will be taken at Cycle 3. 
 
These samples will be centrally analysed for the assessment of of p-Akt, and other potential biomarkers 
related to the PI3K/Akt pathway in tumour. 


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Collection of tumour biopsy is recommended in order to confirm that target inhibition is also 
occurring in the tumour. This should be particularly encouraged for tumours that can be readily 
biopsied. 
8.5.6 Safety Assessment 
Safety and tolerability endpoints will be derived from the following measurements/evaluations: 
• Incidence, intensity, CTCAE v4.03 grading, seriousness and treatment-causality of Treatment 
Emergent Adverse Events (TEAEs). 
• Frequency of clinically significant abnormalities in: 
o Physical examination and vital signs. 
o Safety laboratory tests. 
o 12-lead ECG record. 
o Urinalysis. 
o ECHO or MUGA scan. 
8.5.6.1 Medical History 
Complete medical history will be collected during the Screening Period in order to obtain all information 
necessary to confirm the study inclusion and exclusion criteria.  
General medical history shall include all the diseases (excluding breast cancer) and conditions, either 
chronic or not, which are needed to assess the compliance with inclusion/exclusion criteria and those 
which are relevant according to the Investigator. 
The BC specific medical history will include: date of onset of primary tumour, histology, Ki67 level, 
date of diagnosis of metastatic disease, histology of the metastasis if available, number and type of 
previous treatments and duration of the response to the last treatment.  
General medical history shall be collected starting from 30 days prior to Screening. 
BC specific medical history shall be collected starting from the primary BC onset date. 


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8.5.6.2 Physical Examination and Vital signs  
A complete physical examination (including also neurological examination) will be performed at 
Screening,  and throughout the study at each study visit . It will include a general appearance 
observation and a complete examination of the following body systems/areas: Head, Eyes, Ears, Nose 
and Throat (HEENT)/Neck, Lymph Nodes, Thyroid, Abdomen, Skin, Cardiovascular, Respiratory, 
Gastrointestinal, Neurological and Musculoskeletal/Extremities. 
Vital signs will be recorded throughout the study at each study visit from Screening to End of Study 
Visit. The following parameters will be measured: 
• Heart rate; beats/minute. 
• BP; systolic and diastolic, mmHg. 
• Respiratory rate; breaths/minute. 
• Body temperature; (T; °C). 
8.5.6.3 Weight measurement 
Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) will be measured 
during the Screening Period and at any study treatment administration visits. 
8.5.6.4 Performance Status Evaluation 
PS evaluation will be performed at each study visit from Screening to End of Study Visit using the 
ECOG status (see Table 2). 


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Table 2. 
ECOG Performance Status 
Grade ECOG 
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 house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.  
5 
Dead. 
ECOG = Eastern Cooperative Group 
8.5.6.5 Clinical Laboratory Evaluation 
Safety laboratory assessments will be performed in fasting condition as reported in Sections 2.2 
and 2.3. Beta human chorionic gonadotropin (β-HCG) pregnancy test will be performed in serum, if 
applicable, during the Screening Period, at Visit 1 of each cycle and at the End of Study Visit. 
Urinalysis will be assessed at Screening, at Visit 1 of each cycle, and at the End of Study Visit. The 
assessment of anti-HIV antibodies, anti-HBcAg antibodies, anti-HBsAg antibodies, HBV-DNA, 
HCV-RNA will be performed ONLY during the Screening Period. Safety tests will be performed by 
the local laboratory of participating sites in order to ensure prompt subject management. For the same 
reason, tests for anti-HIV antibodies, anti-HBcAg antibodies, anti-HBsAg antibodies, HBV-DNA, 
HCV-RNA will be performed by local laboratory of participating sites according to local standard 
procedures. In case the laboratory tests for anti-HIV antibodies, anti-HBcAg antibodies, anti-HBsAg 
antibodies, HBV-DNA, and HCV-RNA have been performed within 3 months prior to Screening 
Period in the context of the standard subject’s management (either in the local lab or in a different 
lab, provided that they comply with local standard procedures), they can be reported in the eCRF 
under Screening Period procedures and in the subject file as a source document, and these tests will 
not be repeated. 
Laboratory values have to be transcribed into the eCRF, except for urinalysis for which, only the 
judgement has to be reported in the eCRF; the Sponsor will be provided with the currently valid 
version of the respective normal ranges by the site laboratories (any update of reference ranges needs 
to be notified on an ongoing basis). 


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The lab print-outs should be identified with the subject number. All print-outs should be dated and 
signed by the Investigator and stored in the subject’s record. Any out of range value shall be clinically 
assessed by the Investigator. 
The volume of blood to be drawn for each set of safety lab tests will amount to a maximum of 15 mL. 
The following tests will be performed (Table 3). 
Table 3. 
Blood and Urine Sample Analyte Listing 
Biochemistry 
Serum Virology 
Haematology 
Coagulation  
Urinalysis* 
• 
Creatinine 
• 
Uric acid 
• 
Potassium 
• 
Phosphorus 
• 
Calcium 
• 
BUN/Urea 
• 
Albumin 
• 
ALP 
• 
Glucose 
• 
HbA1c 
• 
Total Proteins 
• 
Total Bilirubin  
• 
Direct Bilirubin 
• 
ALT and AST 
• 
LDH 
• 
GGT 
• 
Amylase 
• 
Lipase 
• 
Sodium 
• 
Chloride 
• 
β-HCG (if 
applicable) 
• 
Anti-HIV antibodies 
• 
Anti-HBcAg antibodies 
• 
Anti-HBsAg antibodies 
• 
HBV-DNA 
• 
HCV-RNA 
• 
Haemoglobin 
• 
Haematocrit  
• 
RBC count 
• 
Platelet count 
• 
MCV 
• 
WBC count 
and 
differential 
(absolute and 
percentage) 
• 
Neutrophil  
• 
Lymphocyte 
• 
Eosinophil 
• 
Basophil 
• 
Monocytes 
• 
INR 
• 
Prothrombin time 
and/or prothrombin 
activity 
• 
Partial 
thromboplastin 
time 
• 
pH 
• 
Density  
• 
Nitrite 
• 
Proteins 
• 
Glucose 
• 
Ketones 
• 
RBC 
• 
WBC 
• 
Epithelial cells 
• 
Casts 
• 
Bacteria 
• 
Yeast 
• 
Crystals 
ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea 
nitrogen, DNA = deoxy ribonucleic acid, GGT = gamma glutamyl transferase HbA1c = glycated haemoglobin, 
HBcAg = hepatitis B core antigen, HBsAg = hepatitis B surface antigen, HCG = human chorionic gonadotropin, 
HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, INR = international 
normalised ratio, LDH = lactate dehydrogenase, MCV = mean corpuscular volume RBC = red blood cell, 
RNA = ribonucleic acid, WBC = white blood cell 
*Urinalysis will be performed at the local laboratory and will include: pH, density, proteins, glucose, ketones, nitrite and 
microscopy when required (i.e., RBC, WBC, epithelial cells, casts, bacteria, yeast and crystals). 


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8.5.6.6 12-Lead Electrocardiogram 
Twelve-lead ECGs will be performed locally, using standard equipment available at the study sites, 
during the Screening Period and during the treatment cycles (see section 8.5.1 and 8.5.2. for 
timepoints). A standard 12-lead ECG will be performed at rest in the supine position. All ECG print-
outs should be identified with subject number, year of birth, as well as with the date and time of 
recording. All print-outs should be assessed, dated and signed by the Investigator and stored in the 
subject’s record. Echocardiogram (ECHO)/Multi-Gated Acquisition (MUGA) scan 
Either an ECHO or MUGA scan will be carried out during the Screening Period, the treatment cycles 
(see section 8.5.1 and 8.5.2. for timepoints) and at End of Study Visit (if not performed in the previous 
14 days). The same technique as used at Screening should be used throughout the study. Only 
clinically relevant findings will be recorded in the appropriate eCRF section. The original 
traces/scans, clearly identified with subject number, year of birth, as well as with the date and time 
of recording, should be assessed, dated and signed by the Investigator and stored in the subject’s 
record. In case of abnormal ECHO/MUGA scan findings of concern, a specialist evaluation should 
be required accordingly with the Investigator judgement. 
8.5.7 Study Endpoints 
8.5.7.1 Primary Endpoints 
Step 1 (Dose-escalation Phase) 
• Identification of MTD, defined as the highest dose level at which no more than 1 of 6 subjects 
experience a DLT during the DLT assessment window (28 day). 
• Identification of DLT, defined as any of the following ADRs related to the combination 
regimens or to MEN1611 alone and unrelated to the subjects’ underlying disease or 
concomitant medication occurring during 28 days after the fisrt MEN1611 administration: 
o Any grade 3 (lasting > 7 days) or grade 4 increase in aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase (ALP). In subjects with hepatic 
metastases, AST or ALT >8x ULN or AST or ALT >5x ULN for ≥14 days is considered 
a DLT. In subjects with grade 2 AST, ALT, or ALP levels at baseline, an elevation to ≥ 
10 × upper limit of normal (ULN) is considered a DLT.  
o Any grade 3 (lasting > 7 days), or grade 4 if asymptomatic, amylase and/or lipase. 
o Any grade ≥ 3 cardiac toxicity or new segmental wall-motion abnormalities. 
o Any other non-haematological toxicity grade ≥ 3 on NCI CTCAE v4.03 (lasting > 7 days) 
with the following exceptions: 
 Nausea. 


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 Vomiting. 
 Diarrhoea. 
 Skin rash. 
 Hyperglycaemia. 
Note: Nausea, vomiting and diarrhoea will be considered a DLT if grade ≥ 3 for more than 
72 hours with adequate antiemetic and other supportive care. Skin rash and hyperglycaemia 
will be considered DLT if they reach grade ≥3 despite adequate treatment as per the institution 
guidelines. 
o No recovery from a non-DLT relative to the above exceptions of grade ≥ 3 toxicity to 
grade ≤ 2 for more than 14 days.  
o Febrile neutropenia (ANC < 1.0 × 109/L and fever ≥ 38.5°C) and/or documented infection 
with ANC < 1.0 × 109/L. 
o NCI CTCAE v4.03 grade 4 neutropenia (ANC < 0.5 × 109/L) lasting ≥ 7 days. 
o NCI CTCAE v4.03 grade ≥ 3 thrombocytopenia (platelets < 50 × 109/L) with bleeding, 
lasting ≥ 7 days and grade 4 thrombocytopenia (platelets < 25 × 109/L) associated with or 
without non traumatic bleeding, or bleeding requiring platelet transfusion. 
o Grade ≥3 fatigue lasting > 1 week. 
o Grade ≥3 electrolyte abnormalities that last more than 72 hours unless the subject has 
clinical symptoms, in which case all grade ≥3 abnormalities regardless of duration should 
count as a DLT. 
o Any NCI CTCAE v4.03 grade 4 (life-threatening consequences; urgent intervention 
indicated) anaemia lasting ≥ 7 days. 
o Any death not clearly due to the underlying disease or extraneous causes. 
o Final effective dose of MEN1611 is administered < 80% and/or trastuzumab and/or 
fulvestrant are administered < 100% of the total scheduled dose for safety reason. 
o Any other study treatment-related toxicity considered significant enough to be qualified 
as DLT in the opinion of any of the Investigators. 
Throughout Step 1, although dose-escalation is primarily based on the incidence of DLTs during the 
first 4 study weeks, toxicities that meet criteria for DLTs and are observed over  the subsequent weeks 
are also taken into account for the assessment of toxicity and the definition of maximum dose judged 
to be tolerable. 
Step 2 (Cohort-expansion Phase) 
• Confirmation of RP2D, defined as MTD or the maximum dose judged to be tolerable. 


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8.5.7.2 Secondary Endpoints 
• Response Rate defined according to RECIST v1.1 (35) as per local and centralised blinded 
independent reading on CT scan or MRI of the chest and abdomen (including pelvis and 
adrenal glands). Any other areas of disease involvement should be additionally investigated 
based on signs and symptoms of individual subjects.  
For the baseline assessment, CT scan or MRI should be performed no more than 6 weeks 
before the treatment start. Follow-up assessment will be performed every 8 weeks during 
study treatment starting from Day 1 Cycle 1 (within a window of – 7 days) until objective 
disease progression as defined by RECIST v1.1 or at the End of Study Visit. Any other site at 
which new disease is suspected should be appropriately imaged. If an unscheduled assessment 
is performed and the disease has not progressed, subsequent assessments should be performed 
at their scheduled visits. 
• Response Rate defined according to RECIST v1.1 as per central radiology assessments 
performed using CT scan or MRI of the chest and abdomen (including pelvis and adrenal 
glands). 
• 
Disease Control Rate (DCR) defined as percentage of subjects whose disease shrinks or 
remains stable over a certain time period. DCR is the sum of the complete response (CR), 
partial response (PR) and stable disease (SD) rates. 
• Duration of Response defined as time from confirmation of a PR, CR or SD, until the disease 
has been shown to progress following treatment. 
• Progression-free survival (PFS) defined as the number of days between the first study 
treatment administration to the date of first documented disease progression, relapse or death 
from any cause. Responding subjects and subjects who are lost to follow-up are censored at 
their last tumour assessment date. 
• Overall Survival (OS) defined as the number of days between the first study treatment 
administration and death from any cause. 
Note: all secondary end points related to tumour assessment will be analysed considering both 
local and central radiology assessments by independent blinded review. 
8.5.7.3
 


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8.5.7.4 Pharmacokinetic Endpoints 
The following PK variables will be assessed: Cmax, tmax, Clast, tlast, Ctrough, ke, t1/2, AUC(0-t), AUC(0-∞), 
%AUCex, CL/F, Vss/F, and Vd/F. PK parameters will be calculated after single and repeated dose 
administration. 
8.5.7.5 Safety Endpoints 
• Incidence, intensity, CTCAE v4.03 grading, seriousness and treatment-causality of TEAEs. 
• Frequency of clinically significant abnormalities in physical examination, safety laboratory 
tests, urinalysis, vital signs, ECHO or MUGA scan and 12-Lead ECG. 
 
Adverse Event Definitions, Monitoring/Recording and Management 
8.6.1 Definitions 
8.6.1.1 Adverse Event (AE) 


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Any untoward medical occurrence in a subject or clinical study subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.  
8.6.1.2 Drug Relationship 
The relationship between an AE and study treatments will be judged according to the following 
categories: 
1. Certainly related: The event or laboratory test abnormality (AE) with plausible time relationship 
to the drug intake and it cannot be explained by a concurrent disease or other drugs. The response 
to withdrawal of the drug (dechallenge) should be plausible (pharmacologically, pathologically). 
The event must be definitive pharmacologically or phenomenologically (i.e., an objective and 
specific medical disorder or a recognised pharmacological phenomenon), using a satisfactory 
rechallenge procedure if necessary. 
2. Probably related: The event or laboratory test abnormality (AE) with reasonable time 
relationship to the drug intake, it is unlikely to be attributed to a concurrent disease or other drugs 
and it follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge (AE 
reappearance after drug reintroduction) is not required. 
3. Possibly related: The event or laboratory test abnormality (AE) with a reasonable time relation 
to the drug intake, but it could also be explained by disease or other drugs. Information on drug 
withdrawal (dechallenge) may be lacking or unclear. 
4. Unassessable/Unclassifiable: The relationship cannot be judged, because of the information is 
insufficient or contradictory and data cannot be supplemented or verified. 
5. Unlikely related: The event or laboratory test abnormality (AE), with a time to drug intake that 
makes a relationship improbable (but not impossible). Disease or other drugs provide plausible 
explanations. 
Not Related: The event or laboratory test abnormality (AE), with a time to drug intake with an 
unreasonable relationship and or non-plausibility and/or the existence of a clear alternative explanation.  
Treatment-Emergent Adverse Events 
AEs will be categorized as Treatment-Emergent Adverse Events (TEAE) or Non-TEAE. If an AE occurs 
for the first time or if it worsens in terms of seriousness or severity after the first study drug intake (either 
MEN1611, trastuzumab or fulvestrant or their combination) it will be classified as TEAE, otherwise it 
will be classified as non-TEAE or clinical event. 


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8.6.1.3 Adverse Drug Reactions (ADRs)  
Any untoward and unintended responses to an investigational medicinal product related to any dose 
administered. The definition covers also medication errors and uses outside what is foreseen in the 
protocol, including misuse and abuse of the product. 
The definition implies a reasonable possibility of a causal relationship between the event and MEN1611, 
trastuzumab, fulvestrant or any of their combinations. This means that there are facts (evidence) or 
arguments to suggest a causal relationship. 
ADRs are considered all AEs for which the relationship is considered as: 
1. Certainly related 
2. Probably related 
3. Possibly related 
4. Unassessable/Unclassifiable 
AEs are not considered as ADRs when the relationship is judged as: 
1. Unlikely related 
2. Not related 
8.6.1.4 Seriousness 
Any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life-threatening; 
“Life-threatening” means that the subject was at immediate risk of death at the time of the 
SAE (Serious Adverse Event); it does not refer to a SAE that hypothetically might have caused 
death if it was more severe. 
• Requires in-subject hospitalisation or prolongation of existing hospitalisation; 
This means that hospital inpatient admission or prolongation of hospital stay were required 
for the treatment of the SAE or that they occurred as a consequence of the event. 
Visits to a hospital by ambulance or to the emergency room without admission will not be 
regarded as hospitalization unless the event fulfils any other of the seriousness criteria.  
• Results in persistent or significant disability/incapacity; 
“Persistent or significant disability or incapacity” means a permanent or significant and 
substantial disruption of a person’s ability to carry out routine activities. 
• Results in congenital anomaly/birth defect; 


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• Is other medically important condition that may jeopardise the subject or may require 
intervention to prevent one of the outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurs. Important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the definition 
above should also usually be considered serious. 
Note: These characteristics/consequences have to be considered at the time the event occurs. For 
example, regarding a life-threatening event, this refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe.  
Any other AE/ADR which is not included in the above definitions will be considered as non-serious. 
Note: Hospitalisation lasting less than 24 hours or pre-planned hospitalisation for diagnostic 
procedures or medical intervention, such as chemotherapy administration, shall not qualify as SAE.  
8.6.1.5 Adverse Event (AE)/Adverse Drug Reaction (ADR) Intensity (Severity) 
Each event will be graded for severity using the classifications of NCI CTCAE v4.03. For events not 
addressed in the NCI CTCAE v4.03 classifications, the following grading will apply:  
• Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Moderate (Grade 2) - Moderate; minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental activity of daily living. 
• Severe (Grade 3) - Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activity of daily living. 
• Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention indicated.  
• Death (Grade 5) - Related to adverse event.   
8.6.1.6 Adverse Drug Reaction (ADR) Expectedness 
An ADR is considered unexpected when the nature, intensity, or outcome of which is not consistent with 
the applicable product information provided in the Reference Safety Document (MEN1611 
Investigator’s Brochure in force, trastuzumab SmPC and fulvestrant SmPC). 
8.6.1.7 Suspected Unexpected Serious Adverse Reaction (SUSAR) 


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Any SAE judged by the Investigator or the Sponsor as drug-related (see Section 0) and considered as 
unexpected is qualified as a Suspected Unexpected Serious Adverse Reaction (SUSAR). 
SUSARs are subject to expedited reporting, as specified in Section 8.6.3.2, as having a “Reasonable 
Possibility” of relationship with the study treatment (MEN1611, trastuzumab, fulvestrant or any of their 
combinations). 
8.6.2 Monitoring and Recording of Adverse Events 
At each visit, the Investigator will assess any occurred subjective or objective AE, starting from the 
informed consent signature to the End of Study Visit. From cycle 5 onwards, the occurrence of Es will 
also be recorded by weekly phone calls between study visits.   
AEs communicated by the subject or by the subject’s relatives or delegates through phone calls, letters 
or e-mails will also be recorded. In these cases, the Investigator will try to obtain medical confirmation 
and assessment of the occurred AE. 
When an AE has occurred, the Investigator shall record it on the respective eCRF-AE recording 
pages, whether serious or non-serious and whether or not thought to be drug-related, observed 
in or reported by the subject (or relatives/delegates), specifying his/her judgement on the causal 
relationship with the study treatment. 
Any available information and diagnostic measure (laboratory and instrumental tests, procedures, 
etc.) shall be recorded in the eCRF, also including those performed in Unscheduled Visits and 
required for AE diagnosis 
In addition, if after the end of the study, the Investigator becomes aware of any new or not reported SAE 
or non-serious AEs of special interest or follow-up of these kind of events already recorded with a 
plausible causal relationship with the study treatment, this information must be recorded in the eCRF 
until it is available.  
Progression of the disease under study will not be captured as an AE.  
 
8.6.3 Management of Serious Adverse Events (SAEs) 
8.6.3.1 Reporting Duties of the Investigator 
The Investigator must record and save all the available information concerning any SAE (whether or not 
deemed related to any of the study treatments) in the corresponding section of the eCRF: eCRF-AE 
pages, no later than 24 hours after the first knowledge of the occurrence of the event. 
When the site personnel enter a new SAE/Case in the eCRF, an automatic alert notification will be 
generated and sent to the Sponsor’s Study Drug Safety Manager (SDSM).  


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The Investigator will be provided with the paper CRF-SAE form to be used only in case of breakdown 
of the eCRF system. In such case, the Investigator will be responsible for sending the paper CRF-SAE 
form as described below no later than 24 hours after the first knowledge and subsequently entering the 
data in eCRF as soon as the system works again.  
Whenever the paper CRF-AE forms are used, they must be submitted by e-mail to the Sponsor’s SDSM:  
Sponsor’s SDSM contact details: 
 
Alfons XII, 587 
08918 Badalona (Barcelona), Spain 
Phone: 
 
Mobile:
 
E-mail: sdsu@menarini.es / 
 / 
For the initial SAE, the Investigator should enter at least the following data: 
• AE medical term. 
• Seriousness criteria. 
• Causality assessment.  
• Study Code and Subject Identification (subject ID) [when the paper CRF-SAE form is used]. 
• Reporter’s name and telephone number for clarification [when the paper CRF-SAE form is 
used]. 
If not already reported, the full description of the event and outcome must follow within 1 working day. 
The Sponsor’s confirmation of reception of the SAE report must be kept in the subject’s records.  
Any questions arising during the processing and medical review of the SAE will be managed by 
means of electronic queries (i.e., queries in the eCRF). In case of a breakdown of the eCRF system, 
queries will be sent by e-mail.  
Any information provided by the Investigator as a query reply or as a follow-up SAE report will be 
processed in the same way as the initial SAE report, within the required timeframe.  
When relevant, the eCRF pages concerning medical history, concomitant medication and laboratory 
tests will also be retrieved by the Sponsor’s SDSU. 
Any further significant information and supporting documentation that become available (such as 
copies of laboratory reports, tests, procedures, autopsy evidence of the cause of death, etc.) shall be 
entered in the eCRF or provided by e-mail to the Sponsor’s SDSM (in case of eCRF unavailability), 
no later than 24 hours after they become known by the Investigator. 


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The Investigator must also comply with the local applicable obligation(s) on the reporting of ADRs 
to the local concerned IRBs/ECs if required, according to the specific country requirements. 
8.6.3.2 Reporting Duties of the Sponsor 
The Sponsor has appointed a centralized Study Drug Safety Unit (SDSU) team to the study, 
encompassing the Study Drug Safety Manager, the Study Drug Safety Manager Deputy, a 
Pharmacovigilance Technician and a Study Drug Safety Assistant. The SDSU team will be 
responsible for the management of AEs from all the sites in compliance with the applicable regulatory 
requirements (including SAEs and SUSARs management) and all safety communications submitted 
to the sites, RAs and ECs accordingly to the procedures described in the corresponding study Safety 
Management Plan (SMP). 
In addition, the Sponsor shall ensure that all relevant information about any suspected serious and 
unexpected adverse reaction (SUSAR) is expeditiously reported to the CAs (including Eudra 
Vigilance Clinical Trial Module for clinical trials for which an EudraCT number has been assigned) 
and ECs (following general and local rules and procedures). The deadlines to be complied with, 
starting on the date of first knowledge, intended as the day when the Sponsor’s SDSU or CRO 
receives the notification of the SUSAR, are the following: 
• Fatal and life threatening unexpected cases, no later than 7 days; 
• Other unexpected serious cases, no later than 15 days. 
The Sponsor shall ensure that all relevant new information is also expeditiously reported as follow-
up information within 15 days for all cases. 
The following safety issues will be subjected to expedited management for the identification of 
possible necessary actions: 
• SAEs associated with the study procedures; 
• Potential clinically significant findings emerging from non-clinical studies; 
• An anticipated end or suspension for safety reasons of another study with the same study 
treatment. 
When appropriate and applicable as per local regulatory requirements, the Sponsor will arrange the 
adequate information also to be sent to the Investigators. The Sponsor (through the SDSU) will 
distribute the validated CIOMS I or Medwatch (for USA) form to the investigators (via e-mail) with 
a safety letter. 
Note: For SUSARs occurred in other on-going studies with MEN1611, if any, the Sponsor will 
comply with the expedited reporting to the ECs and CAs involved in MEN1611-01 study. 


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Note: The Sponsor will be responsible for expeditiously reporting SUSAR cases attributable to 
trastuzumab or fulvestrant, following the procedure described in the SMP, and informing the 
corresponding MAH (as per SmPC details) of the case and of the expedited reporting done. 
8.6.4 Management of Non-Serious Adverse Events and/or Laboratory 
Abnormalities 
The Investigator must record all the available information concerning any non-serious AE (whether 
or not deemed related to the study treatment) in the corresponding section of the eCRF: eCRF-AE 
pages, within 5 calendar days after the first knowledge of the occurrence of the event (including 
those performed in Unscheduled Visit and required for AE diagnosis). 
When the site personnel enters a new AE/case in the eCRF, an automatic alert notification is generated 
and sent to the Sponsor’s SDSM.  
When relevant for the correct assessment of the case, eCRF pages concerning medical history, 
concomitant medication and/or laboratory test, including any updates, will also be retrieved by the 
Sponsor’s SDSM. 
Any further significant information and supporting documentation that become available (such as 
copies of laboratory tests, procedures, etc.) shall also be entered by the Investigator in the eCRF. 
In addition, during the clinical study, clinically significant abnormalities in laboratory analyses, 
urinalysis, physical examination, vital signs or 12-lead ECG, ECHO or MUGA scan or ECOG PS 
(newly occurring after ICF signature or worsening of previously known abnormalities), which are 
considered clinically relevant by the Principal Investigator (such as values significantly above or 
under normal range or which require an intervention or diagnostic tests, or may result in the 
discontinuation of the study treatment), should be reported as AEs. All abnormalities in laboratory 
values should be collected and reviewed by Sponsor on a bi-monthly basis. 
8.6.5 Management of Pregnancy Exposure Cases 
The Investigator is expected to record in a dedicated “Pregnancy Exposure Report Form” any case of 
pregnancy exposure occurring in a female subject or in a female partner of a male subject enrolled in 
the study while participating in the study, occurring during the treatment and follow-up periods. 
The “Pregnancy Exposure Report Forms” are distributed to the sites to be used for this purpose. 
In case of pregnancy, the subject will be withdrawn from the study treatment. The Investigator is 
requested to follow each case of pregnancy exposure until the outcome, provided that the female 
subject or the female partner of a male subject enrolled in the study has signed the related pregnancy 
ICF. 


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The form will be sent to the Sponsor’s SDSM preferably by e-mail within 5 days after the Investigator 
becomes aware of the pregnancy and it is also to be fully completed and sent again within 5 days after 
the outcome is known,  
If the pregnancy results in an abnormal outcome, this will be recorded in the eCRF as an SAE and 
managed as described in Section 8.6.3.1. In case the eCRF is no more available, it will be notified 
through the paper CRF-SAE form and sent to the Sponsor by e-mail 
8.6.6 Management of misuse and overdose cases 
Although study drug misuse and overdose are not considered AEs per sè, both issues should be 
reported to the Sponsor’s SDSU within the same timelines as an SAE, even if they may not result in 
an adverse outcome. In the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
For the purpose of this protocol, an overdose is any dose of the investigational drugs (MEN1611, 
Trastuzumab or Fulvestrant) which is more than the assigned dose level for that subject. The 
corresponding information should be entered in the AE page in the eCRF no later than 24 hours of 
awareness by the site. Once the page is completed and saved by the staff involved in the study, an 
alert notification will be automatically sent to the Sponsor. ONLY if the eCRF system does not work 
or if the eCRF is not available, the paper SAE report form shall be used and sent to the Sponsor by 
email. 
The reporting procedures are described in detail in the SAE report form completion manual 
distributed to the sites. 
In addition, if an AE (serious o non-serious) is associated with an overdose, it will be recorded on the 
AE page in the e-CRF, recording the overdose details. 
If the pharmacy discovers that an overdose has or may have been administered, they should 
immediately contact the Investigator and Sponsor (or their delegate) and let them know. 
8.6.7 Periodic Safety Reporting 
8.6.7.1 Annual Safety Reporting 
Once a year throughout the clinical study, the Sponsor will submit to the concerned national CAs and 
ECs requiring it according to their country specific legislation, a Development Safety Update Report 
(DSUR), taking into account all new safety information received during the reporting period. In the 
US an Investigational New Drug (IND) Report will also be submitted to the FDA, according to the 
applicable legislation. 


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In Europe and USA , the DSUR will be submitted to CAs and ECs by the SDSU within 60 calendar 
days after the Data Lock Point (DLP).  
The IB in force at the start of the reporting period should serve as the reference safety information for 
the document preparation. 
8.6.7.2 Periodic Line-listings Safety Reporting 
All SUSARs occurred in the MEN1611-01 study and/or in any other ongoing trial using MEN1611 
and conducted by Menarini, either in the European Community or in a third country, will be recorded 
in a Line - listing prepared by the SDSU (every 6 months).  
The final Line - listing will be sent to the applicable ECs and Investigators, if and as required per 
country regulations. All Investigators are required to acknowledge their correct reception and reading 
of this information to the Sponsor by e-mail. 
Note: If no SUSARs occur, the Line-listing will not be necessary. 
8.6.8 Safety Issues other than SUSARs 
During the present clinical trial, it may occur that events which do not fall within the definition of 
SUSAR and, thus, are not subject to the reporting requirements for SUSARs, are considered relevant 
in terms of subject safety. In general, it could be the case of new events related to the conduct of a 
trial or the development of MEN1611 which are likely to affect the safety of subjects (e.g.: a SAE 
which could be associated with the trial procedures and which could modify the conduct of the trial, 
major safety findings from newly completed animal studies, such as carcinogenicity, or non-serious 
AEs of special interest as per DSC indication).  
The procedure in such cases should be the following: the SDSU will urgently inform the Menarini 
Project Team (MPT) and the Global Director of Clinical Sciences (GDCS) in order that the 
appropriate actions are immediately taken (e.g.: urgent measures and their notification to the 
authorities, a substantial amendment to the protocol or the early termination of the trial if necessary). 
Moreover, the Sponsor shall inform the National Competent Authority as well as the concerned 
IRBs/ECs and participating investigators of any safety issues which might materially alter the current 
benefit-risk assessment of the study IMP.  
For SUSARs occurred with non-IMP (e.g. concomitant medication) the investigators will be 
encouraged to follow the post-marketing pharmacovigilance rules according to the country 
requirements. Any SUSAR attributable to trastuzumab or fulvestrant will be expeditiously reported 
as described in the relevant chapter. The corresponding MAH will be notified on the case and the 
expedited reporting done.  


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8.6.9 Breaking of the Randomisation Code 
Breaking of the Randomisation Code procedure is not applicable to this study. 
8.6.10 Serious and Non-Serious Adverse Events Follow-up 
After the End of Study Visit, the Investigator is not requested to actively follow-up the subject unless 
ongoing SAEs or non-serious AEs of special interest (as per the Safety Review Committee [SRC]) 
are present. However, if after the end of the study the Investigator becomes aware of any SAEs with 
a suspected causal relationship to the study treatment, they should be duly reported to the Sponsor. 
These SAEs should be recorded in the eCRF if it is available. If the eCRF is not available, the paper 
CRF-AE form will be used as a backup.  
Subjects who discontinued the treatment for safety reason will be followed until the event disappears, 
the subject’s condition stabilises, or until recovery from all toxic effects and longer in case of expected 
delayed toxicity. 
 
Safety Review Committee 
A Safety Review Committee (SRC) will be established consisting of the Principal Investigator(s) and 
the Sponsor’s qualified Medical Representative(s), as well as invited experts (such as Statistician and 
Pharmacokineticist), as appropriate. The SRC is responsible for reviewing and evaluating all the 
available safety data, any DLTs, PK and PD data collected during Step 1 in order to confirm the 
RP2D to be tested in Step 2. The SRC may also meet in ad hoc meetings at its discretion, as needed 
in response to events occurring in the study. Data will be provided to the SRC as described in the 
approved Data Review Plan. Roles and responsibilities of the SRC as well as the meeting schedule 
are provided in a separate SRC Charter. 
8.7.1 Blinded Independent Review Committee 
There will be two Blinded Independent Review Committees (BIRCs) with the aims: 1) to evaluate 
each subject’s CT/MR scans, applying RECIST 1.1 guideline; 2) to evaluate subject’s ECG traces 
collected at selected time points. The details of the execution of the blinded reviews are provided in 
two separate BIRC Charters. 


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9. STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
 
Determination of Sample Size 
A maximum of 18 DLT evaluable subjects need to be enrolled in Step 1 (Dose-escalation Phase).  
During Step 2 (Cohort-expansion Phase), the RP2D will be tested in combination with trastuzumab 
and with trastuzumab and fulvestrant in postmenopausal HR-positive subjects in order to achieve a 
total of 30 subjects (considering also Step 1) in each of the treatment cohorts exposed to the MTD. 
Subjects who drop out prior to be evaluable for DLT during the dose-escalation will be replaced. 
Taking in consideration a 15% drop-out rate, approximately 80 subjects will be enrolled in the study. 
Due to the incidence of PIK3CA mutations and considering the above mentioned drop-out rate, Pre-
screening and Screening failure rates, around 600 HER2-positive a/m breast cancer subjects have to 
be pre-screened. 
 
Analysis Populations 
The following analysis population will be considered in the statistical analysis: 
• DLT population 
All subjects receiving at least 80% of MEN1611 and 100% of trastuzumab and/or fulvestrant 
during cycle 1 with a safety follow-up of 28 days after the first administration. Any subject 
that has experienced a DLT will also be considered evaluable. 
Subjects enrolled in the Dose-escalation Phase who are not DLT evaluable will be replaced. 
• Safety population 
All subjects receiving at least 1 dose of MEN1611. 
• Efficacy population 
All eligible subjects who receive at least 8 weeks of treatment and have at least 1 disease 
assessment are to be considered evaluable for efficacy. 
• PK population  
All subjects receiving the study treatment and with reliable drug assay data relevant for the 
PK parameter of interest. 
 
Statistical Analysis 
9.3.1 Descriptive Statistics 


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All study variables (with the exception of PK variables) will be presented by dose cohort and overall, 
using the appropriate descriptive statistics according to the variable nature, unless otherwise 
specified: 
• Continuous variables: number of non-missing observations, arithmetic mean, standard 
deviation, minimum, median, and maximum. 
• Categorical variables: number of non-missing observations and column percentages (N, %). 
• Time to event variables: number of non-missing observations, number and percentage of 
censored observations, 1st quartile, median (and its 95% confidence interval [CI]), 3rd quartile, 
Kaplan-Meier survival curves. 
The behaviour over time of study variables will be summarised by treatment cohort and overall as 
follows: 
• Continuous variables: descriptive statistics for each time point and for the absolute/percentage 
differences to baseline. 
• Discrete variables: descriptive statistics for each time point and shift tables to baseline. 
Correlation among subject’s variables will be evaluated calculating the appropriate correlation 
coefficient with the respective statistical significance level. 
9.3.2 Pharmacokinetic Analysis 
The PK analysis will be performed on the PK population. All PK variables (i.e., MEN1611 plasma 
concentrations and parameters) will be summarised by cohort using the following descriptive 
statistics: 
• Number of non-missing observations (N). 
• Arithmetic mean and its 90% CI, standard deviation, coefficient of variation (CV%) and 
standard error (SE). 
• Geometric mean (GM) and its 90% CI and GM CV%.  
• Minimum, median, maximum. 
MEN1611 plasma concentrations will be summarised for each scheduled sampling time point using 
descriptive statistics. Individual plasma concentration data versus time will be presented in a data 
listing and visualised as individual concentration-time plots. 
The analysis of the following exploratory endpoints PK/PD: 


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9.3.3 Efficacy Analysis 
Efficacy analysis will be performed only through descriptive statistics. 
9.3.4 Safety Analysis 
Safety analysis will be performed on the safety population through descriptive statistics during each 
study phase. Summary statistics will report the incidence of the AEs by CTC toxicity grade, dose 
level, relationship to study treatment and overall. Counts and percentages will be reported for the 
results of ECG, laboratory values, vital signs, physical examination, all classified as 
Normal/Abnormal Not Clinically Significant/Abnormal Clinically Significant by dose level and visit. 
Descriptive statistics will also be produced for the extent of exposure, overall drug administration, 
drug administration by dose level and dose delay by dose level. 
9.3.5 Data imputations 
Missing values will not be imputed since for every analysis an observed-cases approach will be 
applied. 
 
Protocol Violations and Data Review Meeting 
Categories of protocol violations will be defined and will be integrated in the statistical analysis. 
A data review meeting (DRM) will take place at the end of the study in order to evaluate and accept 
the data management report, discuss remaining issues (outstanding queries, unresolved errors) and to 
confirm and approve relevant protocol violations. After this final DRM has taken place and the 
database is considered cleaned, the database will be locked. 
 
Statistical Analysis Plan 
The statistical analysis plan (SAP) will be finalised before the lock of the study database. The SAP 
will describe in detail study endpoints and the statistical analyses, including the statistical analysis of 
the primary endpoint to be performed, as well as additional endpoints and analyses not planned in the 
protocol. In case changes of the original primary endpoint or of the original primary analyses will 
occur during the study, these changes will be the subject of a substantial protocol amendment.  


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A Data Review Plan will be finalised before the start of the study. The Data Review Plan will describe 
the data that will be provided to the Investigators before every DSMB meeting. All statistical analyses 
not pre-specified and run after data lock will be considered additional/exploratory analyses.  


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10. DATA QUALITY MANAGEMENT 
 Data Collection 
Data collection activities will be carried out under the responsibility of the Sponsor. Subject data will 
be collected using an Electronic Data Capture system (EDC; see Section 10.1.1). Subjects will be 
identified by the study identification number (subject ID), assigned during the Screening Period.  
The subject ID will be a number composed of 8 digits CCCSSPPP:  
• CCC is the international phone code of the country (with a leading zero for countries that have 
a 2-digit phone code). 
• SS is the site number in the country: it will start from 01 for each country and will be 
ascending. 
• PPP is the subject number in the site; it will start from 001 and will be ascending. 
Data will be collected, processed, evaluated, reviewed and stored in anonymous form in accordance 
with applicable data protection regulations. 
10.1.1  Electronic Case Report Form 
Clinical data collected during the study at sites will be recorded in an eCRF using Medidata RAVE 
which is a validated system. The Sponsor will be responsible to develop the eCRF based on this study 
protocol and to review and perform the user acceptance test of the eCRF in order to ensure protocol 
adherence. 
The eCRF will be made available to the study personnel by means of the iMedidata interface which 
is a validated system. The accounts will be individual and password-protected. 
The Investigator or designee will be responsible for entering study data into the eCRF in accordance 
to the eCRF completion guidelines provided by the Sponsor. In order to improve the quality of data 
collection and cleaning, data shall be entered into the eCRF as closely as possible to the time when 
they become available and not later than within 5 working days. The eCRF data will not be considered 
as source data (the definition of the source data can be found in Section 10.3). 
Investigators will ensure the accuracy, completeness and consistency of data entered signing 
electronically the eCRF using the personal password. 
An audit trail within the system will track all changes made to the data.  
10.1.2 Interactive Web-response System (IWRS) 
IWRS system ClinPhone RTSM, provided by Parexel International is a validated system used by the 
site personnel for the subject pre-screening (including assignment of the subject number), kit 


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assignment and subject status change. Site staff will be provided with a personal user name and 
password to access to IWRS portal. 
An IWRS user manual will be prepared by Parexel International and provided to site. Details on the 
IWRS provider can be found in the specific manual. Some data such as subject numbers and visit 
dates collected through IWRS system could be automatically integrated in eCRF (the integration 
process will be detailed in a specific integration document). 
10.1.3 Subject Diary 
Subjects are required to record their use of MEN1611 daily intake (including the time of each intake) 
for the whole study duration in a paper booklet (Subject Diary) that will be provided by the Sponsor. 
It is also required to record the time of intake of acid reducing agents whenever administrated as 
concomitant medication. The subject has to bring the diary to the site at each study visit and the 
completed diary pages have to be checked by the Investigator. At each cycle (Visit 1), the completed 
diary will be collected and data entered into the eCRF. The Investigator or designee will be 
responsible for entering diary data into the eCRF. At the same time, a new diary will be dispensed to 
the subject for completion. 
In the exceptional situation in which MEN1611 Subject Diary retrieval is unattainable, the 
Investigator will be responsible for documenting drug accountability as per his/her knowledge.   
10.1.4 Central Laboratory/Examination data 
Central laboratories data will be managed according to laboratory SOPs and will be transferred to 
Menarini Ricerche SpA, Clinical Sciences department for statistics and PK analyses. Sites will 
receive from central laboratories only reports related to PIK3CA mutational analysis of FFPE. 
Imaging data used for tumour assessments and ECG traces will be collected at the sites, transmitted 
to designated vendors for centralized analysis, quality control, as well as further processing and data 
reconciliation. They will be retrospectively reviewed by the BIRCs. 
Details on the collection, handling and shipment of samples will be provided in a separate Laboratory 
Manual prior to the start of the study. 
10.1.5  Data Capture Systems Versions and Validation Documentation 
Versions of the data capture systems can change during the study. The Sponsor will maintain a list of 
the data capture system versions used and the validation documentation of each version. The list and 
the validation documentation will be provided to the site at the site initiation visit and will be updated 
at any data capture system version change. 


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 Clinical Data Management 
Data Management will be carried out under the responsibility of the Sponsor. 
The eCRF data will be electronically verified through the use of on-line and off-line checks. 
Discrepancies in the data will be resolved by means of electronic queries. Data will be locked by the 
data manager when all activities for the study, including medical revision of the data, are complete 
and no more entries are expected.  
Data from sources other than the eCRF will be provided to the data manager on an agreed scheduled 
basis. The data manager has the responsibility to reconcile data captured in the eCRF, with external 
data sources. Discrepancies found in the reconciliation of the data, will be addressed by means of 
queries. 
A clear overview of all clinical data management activities will be given in the data management 
plan. 
 Source Data 
Source data are defined as all data in original records and certified copies of original records of 
clinical findings, observations or other activities in a clinical study that are necessary for the 
reconstruction and evaluation of the study. 
Original documents and data records include, but are not limited to hospital/subjects’ medical records, 
laboratory notes, ECG records, subject’s diary, subjects’ identification forms and pharmacy 
dispensing records. Study sites will also maintain a paper drug accountability forms for the study 
treatment to document dispensed and returned study treatment, as applicable. 
Source data should be held available for perusal by the Sponsor representatives for the study or to 
other authorised persons such as auditors and inspectors of Regulatory Authorities.  
Direct access to source data is defined as the permission to examine, analyze, verify and reproduce 
any records and reports that are important for evaluation of a clinical study (see Section 10.4.1). Any 
party allowed to direct access to study source data and documents should take all reasonable 
precautions within the constraints of the applicable regulatory requirements to maintain the 
confidentiality of subject identities and sponsor proprietary information.  
Data should be consistent with the source documents and discrepancies, if any, should be explained 
in writing. All the original documentation pertinent to the study procedures must be available for 
review in each subject’s record. 


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 Quality Control/Quality Assurance 
10.4.1 Study Monitoring 
This study will be monitored in accordance with the ICH Guidelines for GCP. Monitoring will be 
carried out under the responsibility of the CRO (IQVIATM). The site monitor will perform visits to 
the study sites during the study conduct. Facilities, study treatment, storage area, storage conditions 
for biological samples, eCRF, subject’s source data and all other study documentation will be 
inspected/reviewed by the site monitor for adherence to the protocol and GCP. At each site visit, the 
monitor will review the eCRFs for completion and accuracy. Accuracy will be checked by performing 
source data verification that is a direct comparison of the entries made onto the eCRFs against the 
appropriate source documentation. Any resulting discrepancies will be reviewed with the Investigator 
and his/her staff. The Investigator agrees to allow access to all study-related materials needed for the 
proper review of study conduct and to assist the monitor during the monitoring visits and during the 
data cleaning process. Monitoring procedures require that 100% of data are source data verified, 
particularly focusing on informed consents, adherence to inclusion/exclusion criteria, drug 
accountability, documentation of SAEs and the proper recording of efficacy and safety 
measurements. All monitoring activities will be described in detail in the study-specific monitoring 
plan. 
10.4.2  Quality Assurance 
Independent study audit(s) and/or inspection(s) may take place at any time during or after the study. 
The independent audit/inspection can be carried by the Quality Assurance (QA) of the CRO, an 
independent QA Department, or a CA. At all times, the confidentiality of subject-related documents 
will be maintained. 


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11. PREMATURE TERMINATION OF THE WHOLE STUDY 
The whole study may be discontinued at the discretion of the Sponsor in the event of any of the 
following: 
• New information leading to unfavourable risk-benefit judgement of the study treatment due 
to: 
o Occurrence of clinically significant unknown AEs or unexpectedly high intensity or 
incidence of known AEs. 
o New evidence of unfavourable safety or efficacy findings (from clinical or non-clinical 
examinations, e.g., toxicology). 
• The Sponsors decision that continuation of the study is unjustifiable for medical or ethical 
reasons. 
• Discontinuation of development of the study treatment. 
CAs and IRB/IECs will be informed about the discontinuation of the study in accordance with 
applicable regulations. 


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12. END OF CLINICAL STUDY AND ARCHIVING 
The clinical study will end with the collection and analysis of study data and the issue of the clinical 
study report. All essential documents will be archived by the Sponsor according to the relevant SOP. 
 Archiving of Electronic Documentation/Data 
Duplicate electronic media such as CDs/DVDs (1 for routine access and 1 for back-up) containing 
the subject data in PDF format (i.e., eCRFs) for each site will be prepared by the Sponsor or a delegate 
for archiving purposes. The electronic media, of not re-printable type, will be appropriately labelled 
recording the files/data included. The files should contain at least the e-data copy clearly reporting 
the system name, study code and the eCRF version used; for eCRF data also the electronic signature 
and the associated audit trails have to be included. The Investigator should verify whether the 
provided electronic media represent a complete copy of eCRFs generated during the study. The 
Investigator has to confirm the receipt and correctness of the material by signing a dedicate form 
provided by the Sponsor, the signed form has to be collected and archived in the TMF. Investigators 
will be also responsible for electronic media refreshment approximately every 7 years to ensure long 
term archiving of files/data. Two copies of the same electronic media prepared for the sites or 
cumulative electronic media with the same content will be archived by the Sponsor and refreshed 
approximately every 7 years to ensure long term archiving of files/data. In addition the Sponsor is 
responsible to create 2 electronic media (1 for routine access and 1 for back-up) containing an 
integrated Statistical Analysis System (SAS) database with all study data (e.g. eCRF, IWRS, central 
laboratory), with appropriate refreshment procedures. 
 
 


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13. APPENDICES 
APPENDIX I: Study Procedures ONLY for subjects on weekly trastuzumab 
administration schedule 
The study procedures ONLY for subjects already included in the study at the time this Protocol version 
4.0 is in force are depicted in the Tables 1 to 4 of this appendix and summarised below by Pre-screening 
Period, Screening Period, pre-Cycle 1 (Visit 0 on Day -7, in case the trastuzumab loading dose is 
foreseen) and 28-day Treatment cycles. Each period requires 4-weekly study visits until the End of Study 
Visit. After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status 
according to local practice (a visit or a telephone call) every 12 weeks ± 7 days up to the end of study. 
Pre-screening Period: 
Subjects with HER2 positive a/m breast cancer will be eligible for pre-screening if they have progressed 
to at least one line of trastuzumab based regimen in the a/m setting and: 
• are on an ongoing second line of treatment or 
• have received at least 2 lines of HER2-targeted therapies. 
At the Pre-screening Visit, all subjects will sign the informed consent to perform mutational analysis for 
PIK3CA on the most recent archived FFPE tissue.  
Note: In case no archived tissue sample is available, a new biopsy of the primary tumour or a metastasis 
should only be obtained upon subject consent, and based on the investigators judgment that there is no 
additional risk to the subject’s safety. The samples will be centrally analysed using validated Cobas® 
PIK3CA Mutation Test. 
Screening Period (Day -27 to Day -1): 
During the 28 days prior to the first dose of MEN1611 and following provision of written informed 
consent, each subject will be screened for eligibility. 
The following procedures will be performed at Screening: 
• Check of inclusion/exclusion criteria. 
• Recording of demographic data. 
• Standard medical, surgical and medication history. 
• Smoking history and current status. 
• Verification of pre- or postmenopausal status (see APPENDIX II: Contraceptive Guidance 
and Woman of Childbearing Potential) in HR-positive women. 
• ECOG PS. 


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• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature), height and weight. 
• Recording of AEs and concomitant medications. 
• 12-lead ECG record.  
• Echocardiogram (ECHO) or MUGA scan. 
• Local tumour assessment using Response Evaluation Criteria in Solid Tumours (RECIST) 
(35) version 1.1 (v1.1) with computed tomography (CT) scan or Magnetic resonance imaging 
(MRI) for subjects with measurable disease.  
• Blood samples for haematology, coagulation and chemistry, HbA1c included. Blood sampling 
for anti-HIV antibodies, anti-hepatitis B core antigen (anti-HBcAg) antibodies, anti-hepatitis 
B surface antigen (anti-HbsAg) antibodies, HBV-DNA, HCV-ribonucleic acid (HCV-RNA). 
Note: In case the laboratory tests for anti-HIV antibodies, anti-HbcAg antibodies, anti-HbsAg 
antibodies, HBV-DNA and HCV-RNA have been performed within 3 months prior to 
Screening Period in the context of the standard subject’s management, these tests will not be 
repeated. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
• Optional new tumour biopsy to be performed upon subject’s consent and centrally analysed 
for PD.  
Note: Collection of tumour biopsy is recommended in order to confirm that the target 
inhibition is also occurring in the tumour. This should be particularly encouraged for tumours 
that can be readily biopsied. 
 
A screen failure is defined as follows: 
o A subject who does not meet the eligibility criteria required for study participation 
during the Screening Period. 
o A subject who no longer meets eligibility criteria at study Visits 0 or 1 (i.e., Day ˗7 or 
Day 1 of Cycle 1, when applicable). 
o A subject whose time window between Screening and Visit 1 (i.e., Day 1 of Cycle 1, 
when applicable) is longer than 4 weeks. 
Note: If the complete assessment of the eligibility criteria is available within 3 days from the 
end of the Screening Period, the subject’s eligibility must be confirmed by the Medical 
Monitor. 
Screen failures can be re-screened upon Medical Monitor’s approval. 


Clinical Study Protocol 
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Study Code MEN1611-01 
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A drop-out is defined as a subject who voluntarily withdraws from the study. 
Pre-Cycle 1: 
Optional Visit 0: Trastuzumab loading administration (Day -7) 
Visit 0 is required ONLY if a trastuzumab loading dose is needed, if considered appropriate by the 
Investigator based on the time elapsed from of the last trastuzumab dose received by the subject prior to 
study enrolment. 
(All the following assessments will be performed within 48 hours prior to loading dose 
administration, unless otherwise indicated) 
• Re-evaluation of inclusion/exclusion criteria and confirmation of subject’s eligibility prior to 
the start of study treatment. 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• Blood samples for haematology (no fasted state). 
• Recording of AEs and concomitant medications. 
• Drug administration: 
o Trastuzumab 4 mg/kg loading dose should be administered as a 90-minute IV infusion. 
Notes:  
• If the initial loading dose is well tolerated, the subsequent doses can be administered 
as a 30-minute infusion. 
• Subjects will be monitored at the site for occurrence of AE for at least 6 hours after 
the start of the infusion. 
Cycle 1: 
Visit 1 – start of MEN1611 treatment (Day 1): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Re-evaluation of inclusion/exclusion criteria and confirmation of subject’s eligibility prior to 
the start of the study treatment. 
• Tumour assessment using RECIST v1.1 with CT scan or MRI ONLY if older than 6 weeks.  


Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
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• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• Blood sample for central analysis of tumour markers before the treatment: PIK3CA mutations 
in ctDNA and CTC enumeration. 
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry including HbA1c. 
• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
 
 
 
 
 
  
 
 
• Dispensing of the subject diary for study treatment compliance.  
Note: Subjects will be asked to complete a subject diary for the duration of their treatment 
with MEN1611. 
• Recording of AEs and concomitant medications. 
• Cohort assignment for MEN1611 dose level (only for Step 1). 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 2 mg/kg as a 30-minute IV infusion. 
o Dispensing of MEN1611 and administration 
 of the first assigned 
dose (16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects. 
Note: Subjects will be monitored at the site for occurrence of AE for at least 2 hours after the start 
of the trastuzumab infusion. 
Visit 2 (Day 8), Visit 3 (Day 15) and Visit 4 (Day 22): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry. 


Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
142 of 168  
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• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 2 mg/kg as a 30-minute IV infusion. 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects ONLY at 
Day 15. 
Note: Subjects will be monitored at the site for occurrence of AE for at least 2 hours after 
start of the trastuzumab infusion. 
Cycle 2: 
Visit 1 (Day 1) (+ 5-Day window): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• Blood sample for central analysis of tumour markers before the treatment: PIK3CA mutations 
in ctDNA and CTC enumeration. 
 
 
 
 
• ECOG PS. 
• 12-lead ECG (same technique used at screening). 
• Blood samples for haematology, coagulation and chemistry including HbA1c. 


Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
143 of 168  
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• Serum pregnancy test (if applicable). 
• Sample for urinalysis. 
• Dispensing of the subject diary for study treatment compliance. 
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 2 mg/kg as a 30-minute IV infusion.  
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects. 
Note: Subjects will be monitored at the site for occurrence of AE for at least 2 hours after the 
start of the trastuzumab infusion. 
Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 22): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight.  
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry, ONLY at Day 15. 
 
 
 
  
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 2 mg/kg as a 30-minute IV infusion. 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules respectively). 
Note: Subjects will be monitored at site for occurrence of AE for at least 2 hours after the the 
start of trastuzumab infusion. 
 
Cycle 3 up to Cycle 6:  
Visit 1 (Day 1) (+ 5 Day window) 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
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144 of 168  
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• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• Blood samples for haematology, coagulation and chemistry including HbA1c. 
• Serum pregnancy test (if applicable). 
• Blood sample for central analysis of tumour markers before the treatment: PIK3CA mutations 
in ctDNA and CTC enumeration at Cycle 3 and Cycle 5.  
 
 
• Tumour assessment using RECIST v1.1 will be performed at Cycle 3 and Cycle 5 (- 7-day 
window). 
• Tumour biopsy will be performed on Day 1 of Cycle 3 (± 7 Days) only in subjects who 
underwent the optional assessment at Screening, and centrally analysed for PD. 
• Sample for urinalysis. 
• ECOG PS. 
• ECHO or MUGA scan (same technique used at screening). Will be performed at Cycle 3 and 
Cycle 5 (- 7-day window).  
• 12-lead ECG (same technique used at screening) will be performed at Cycle 3 and Cycle 5.  
• Dispensing of the subject diary for study treatment compliance. 
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 2 mg/kg as a 30-minute IV infusion. 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant 500 mg IM injection in postmenopausal HR-positive subjects. 
Note: Subjects will be monitored at site for occurrence of AE for at least 2 hours after the 
start of the trastuzumab infusion.          
Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 22): 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• Blood samples for haematology, coagulation and chemistry, ONLY at Day 15. 
• Recording of AEs and concomitant medications. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
145 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 2 mg/kg as a 30-minute IV infusion. 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules respectively). 
Note: Subjects will be monitored at the site for occurrence of AEs for at least 2 hours after 
the start of the trastuzumab infusion. 
Cycle 7 Onwards: 
Visit 1 (Day 1) (+ 5-Days window), Visit 2 (Day 8), Visit 3 (Day 15) and Visit 4 (Day 22) 
(All assessments will be performed within 48 hours prior to administration of the study treatment, 
unless otherwise indicated) 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature) and weight. 
• ECOG PS. 
• ECHO or MUGA scan (same technique used at screening) at Day 1 of Cycle 7 and then 
EVERY 2 cycles (- 7-day window). 
• 12-lead ECG (same technique used at screening) at Day 1 of Cycle 7 and then EVERY 
2 cycles.  
• Blood samples for haematology, coagulation and chemistry including HbA1c ONLY at Day 
1 of EACH cycle.  
• Serum pregnancy test (if applicable) ONLY at Day 1 of EACH cycle. 
• Sample for urinalysis ONLY at Day 1 of EACH cycle. 
• Tumour assessment using RECIST v1.1 at Day 1 of Cycle 7 and then EVERY 2 cycles 
(- 7-day window).  
• Blood sample for central analysis of tumour markers before the treatment: PIK3CA mutations 
in ctDNA and CTC enumeration at Day 1 of Cycle 7 and then EVERY 2 cycles. 
• Dispensing of the subject diary for study treatment compliance at Day 1 of EACH cycle. 
• Recording of AEs and concomitant medications. 
• Study treatment administration, according to the following recommended order: 
o Trastuzumab 2 mg/kg as a 30-minute IV infusion. 
o Dispensing of MEN1611 and administration 
 at the assigned dose 
(16, 32 or 48 mg as 1, 2 or 3 capsules, respectively). 
o Fulvestrant (monthly administration) 500 mg IM injection in postmenopausal 
HR-positive subjects. 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
146 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
Note: Subjects will be monitored at site for occurrence of AE for at least 2 hours after the 
start of the trastuzumab infusion. 
Note: For the whole study duration, unscheduled visits can be performed when further assessments 
are required as per the Investigator’s judgement. 
End of Study Visit (4 weeks ± 7 days after last administered dose of MEN1611): 
• Physical examination including vital signs (i.e., BP, heart rate, respiratory rate, body 
temperature). 
• Smoking current status. 
• Tumour assessment using RECIST v1.1 will be performed if the last assessment is older than 
8 weeks. 
• ECOG PS. 
• ECHO or MUGA scan (same technique used at screening), if not performed within the 
previous 14 days. 
• Blood samples for haematology, coagulation and chemistry. 
• Sample for urinalysis. 
• Recording of AEs and concomitant medications. 
• Serum pregnancy test (if applicable). 
• Blood sample for central analysis of tumour markers: PIK3CA mutations in ctDNA and CTC 
enumeration. 
Note: All subjects shall undergo the End of Study Visit at the scheduled day (at time frame of 
± 7 days) or at the time of Study Withdrawal. Unscheduled assessment showing disease progression 
and leading to a subject’s withdrawal can replace the End of Study Visit provided that all 
assessment/procedures scheduled for this visit are completed. 
 
Survival Follow-up: 
After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status 
according to local practice (a visit or a telephone call) every 12 weeks (± 7 days) up to the End of 
Study.


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
147 of 168  
Confidential 
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Table 1. Study Flow-Chart (ONLY for subjects on weekly trastuzumab administration schedule) 
 
PROCEDURE  
Pre-
screening 
Perioda 
Screening 
Period 
Day ˗27 
to Day ˗1 
STUDY VISITS 
pre-
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 3 up to 
Cycle 6 
Cycle 7 
onwards 
End of 
Study 
Visitd 
Follow-
upm 
Visit 0b 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Day ˗7 
Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 
Day window 
 
 
 
+ 5 
 
+ 5 
 
+ 5 
 
Informed consent for PIK3CA 
mutational analysis on archived 
FFPE (or new tumour biopsy) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical and medication 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Smoking history and/or current 
status 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Postmenopausal status in 
HR-positive subjects 
 
X 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
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PROCEDURE  
Pre-
screening 
Perioda 
Screening 
Period 
Day ˗27 
to Day ˗1 
STUDY VISITS 
pre-
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 3 up to 
Cycle 6 
Cycle 7 
onwards 
End of 
Study 
Visitd 
Follow-
upm 
Visit 0b 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Day ˗7 
Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 
Day window 
 
 
 
+ 5 
 
+ 5 
 
+ 5 
 
Physical examination including vital 
signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
 
X 
 
 
 
X 
 
Xe 
 
Xf 
 
 
 
Echocardiography or MUGA 
 
X 
 
 
 
 
 
Xg 
 
Xh 
 
Xi 
 
Tumour assessmentj 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
Optional new tumour biopsyk  
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Blood sampling 
See “Blood and Urine Samples Flow Chart”, “PK Blood Samples Flow Chart” and “PD Hair Follicle and PRP Samples 
Flow Chart” (Tables 2, 3 and 4) 
Urinalysis 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PD assessments 
See “PD Hair follicle and PRP Samples Flow Chart” (Table 4) 
Cohort assignment (only for Step 1) 
 
 
 
X 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
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PROCEDURE  
Pre-
screening 
Perioda 
Screening 
Period 
Day ˗27 
to Day ˗1 
STUDY VISITS 
pre-
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 3 up to 
Cycle 6 
Cycle 7 
onwards 
End of 
Study 
Visitd 
Follow-
upm 
Visit 0b 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Day ˗7 
Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 Day 1 Days 8, 
15, 22 
Day window 
 
 
 
+ 5 
 
+ 5 
 
+ 5 
 
Subject diary dispensing 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
MEN1611 dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
MEN1611 administration  
BID 
Trastuzumab loading dose (if 
required) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Trastuzumab administration 
X 
X 
X 
X 
X 
X 
X 
X 
Fulvestrant administrationl 
X 
Xl 
X 
X 
X 
 
AEs/concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall survival 
 
 
 
 
 
 
 
 
 
 
 
 
X 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
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AE = adverse event, BID = twice daily, CT = computed tomography, ct = circulating tumour, CTC = circulating tumour cell, ECG = electrocardiogram, ECOG PS = Eastern 
Cooperative Oncology Group performance status, DNA = deoxyribonucleic acid, FFPE = formalin-fixed paraffin-embedded, HBcAg = hepatitis B core antigen, HbsAg = hepatitis 
B surface antigen, HBV = hepatitis B virus, HCG = human chorionic gonadotropin, HCV = hepatitis C virus, HIV = human immunodeficiency virus, HR = hormone receptor, 
IM = intramuscular, MRI = magnetic resonance imaging, MUGA = multi-gated acquisition, PD = pharmacodynamic, PIK3CA = Phosphatidylinositol 3-kinase, catalytic, alpha 
polypeptide gene, PK = pharmacokinetic, PRP = platelet-rich plasma, RECIST = Response Evaluation Criteria in Solid Tumours, RNA = ribonucleic acid 
a. 
No time limits. The pre-screening will start as soon as the site is activated. 
b. Visit 0 is required ONLY if a trastuzumab loading dose is needed, if considered appropriate by the Investigator based on the time elapsed from the last trastuzumab dose 
received prior to study enrolment. All the assessments of Visit 0 will be performed prior to loading dose administration, unless otherwise indicated. 
c. 
All assessments will be performed within 48 hours prior to administration of the study treatment, unless otherwise indicated. 
d. End of Study Visit to be performed 4 weeks (± 7 days) after last administered dose of MEN1611. 
e. 
12-lead ECG (same technique used at screening) will be performed at Cycle 3 and Cycle 5.  
f. 
For subjects continuing in treatment beyond Cycle 7, 12-lead ECG will be repeated every 2 cycles Day 1.  
g. Echocardiography or MUGA (same technique used at screening) will be performed at Cycle 3 and Cycle 5 (- 7 days). 
h. For subjects continuing in treatment beyond Cycle 7, Echocardiography or MUGA will be repeated every 2 cycles Day 1(- 7 days). 
i. 
Echocardiography or MUGA (same technique used at screening) if not performed within the previous 14 days. 
j. 
Screening Visit: Tumour assessment, using RECIST version 1.1 with CT scan or MRI for subjects with measurable disease. 
Cycle 1, Visit 1: Tumour assessment, using RECIST version 1.1 with CT scan or MRI for subjects with measurable disease performed in the last 6 weeks. 
Cycle 3 onward, Visit 1 (- 7 days): Tumour assessment using RECIST version 1.1 every 2 cycles. 
End of Study Visit: Tumour assessment using RECIST version 1.1 if the last assessment is older than 8 weeks. 
Imaging data will be collected for retrospective central radiological assessment by a BIRC 
k. Screening Visit: Optional new tumour biopsy will be performed upon subject’s consent and centrally analysed for PD. 
Cycle 3 Visit 1: Tumour biopsy will be performed only in subjects who underwent the optional assessment at Screening, and centrally analysed for PD. 
l. 
Fulvestrant 500 mg IM injection will be administered to HR-positive postmenopausal subjects on Day 1 of every Cycle; another additional dose will be administered on 
Day 15 of Cycle 1. 
m. After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status according to local practice (a visit or a telephone call) every 12 weeks 
±7 days up to the End of Study. . 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
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Table 2.  Blood and Urine Samples Flow Chart (ONLY for subjects on weekly trastuzumab administration schedule) 
 
 
PROCEDURES 
Pre-
screening 
Perioda 
Screening 
Period 
Day ˗27 
to Day ˗1 
STUDY VISITS 
pre-
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 3 up to 
Cycle 6 
Cycle 7 onwards 
End of 
Study 
Visitd 
Follow-
upe 
Visit 0b Visi
t 1c 
Visit 
2c,3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 
4c 
Visit 1c 
Visits 
2c, 3c 
and 4c 
Day ˗7 
Day
 1 
Days 8, 
15 and 
22 
Day 1 
Days 
8, 15 
and 22 
Day 1 
Days 
8, 15 
and 
22 
Day 1 
Days 
8, 15 
and 22 
Day window 
 
 
 
+ 5 
 
+ 5 
 
+ 5 
 
Blood safety lab tests: 
haematology, coagulation, 
chemistryf 
 
Xg 
Xh 
Xg 
X 
Xg 
Xi  
Xg 
Xi 
Xg 
 
X 
 
Serum Pregnancy test (if 
applicable) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Anti-HIV antibodies, anti-HbcAg 
antibodies, anti-HbsAg 
antibodies, HBV-DNA, 
HCV-RNAj 
 
X 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
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Confidential 
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PROCEDURES 
Pre-
screening 
Perioda 
Screening 
Period 
Day ˗27 
to Day ˗1 
STUDY VISITS 
pre-
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 3 up to 
Cycle 6 
Cycle 7 onwards 
End of 
Study 
Visitd 
Follow-
upe 
Visit 0b Visi
t 1c 
Visit 
2c,3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 4c 
Visit 
1c 
Visits 
2c, 3c 
and 
4c 
Visit 1c 
Visits 
2c, 3c 
and 4c 
Day ˗7 
Day
 1 
Days 8, 
15 and 
22 
Day 1 
Days 
8, 15 
and 22 
Day 1 
Days 
8, 15 
and 
22 
Day 1 
Days 
8, 15 
and 22 
Day window 
 
 
 
+ 5 
 
+ 5 
 
+ 5 
 
ctDNA blood sampling 
 
 
 
X 
 
X 
 
Xk 
 
Xl 
 
X 
 
CTC blood sampling 
 
 
 
X 
 
X 
 
Xk 
 
Xl 
 
X 
 


Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
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153 of 168  
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a. 
No time limits. The pre-screening will start as soon as the site is activated. 
b. 
Visit 0 is required only if a trastuzumab loading dose is needed, if considered appropriate by the Investigator 
based on the time elapsed from of the last trastuzumab dose received prior to study enrolment. All the 
assessments of Visit 0 will be performed prior to loading dose administration, unless otherwise indicated. 
c. 
All assessments will be performed within 48 hours prior to administration of the study treatment, unless 
otherwise indicated.  
d. 
End of Study Visit to be performed 4 weeks (± 7 days) after last administered dose of MEN1611. 
e. 
After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status according 
to local practice (a visit or a telephone call) every 12 weeks ±7 days up to the End of Study.  
f. 
Blood safety lab tests (haematology, coagulation, chemistry) to be performed in fasting condition except at 
Pre-Cycle 1 V0 (only haematology required). 
g. 
Blood safety lab tests including HbA1c analysis.  
h. 
Blood samples only for haematology. 
i. 
Blood safety lab tests ONLY at Day 15.  
j. 
There is no need to repeat these tests in case they have been performed within 3 months prior to Screening 
Period in the context of the standard subject’s management. 
k. 
ctDNA and CTC blood sampling only at Cycle 3 and Cycle 5. 
l. 
ctDNA and CTC blood sampling at Day 1 of Cycle 7 and then every 2 cycles. 
 
 


Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
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Clinical Study Protocol 
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Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
155 of 168  
Confidential 
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Clinical Study Protocol 
EudraCT No.: 2017-004631-36 
 
Study Code MEN1611-01 
FINAL Version 5.0,  
03 March 2022 
 
 
156 of 168  
Confidential 
Menarini Ricerche S.p.A. 
 
APPENDIX II: Contraceptive Guidance and Woman of Childbearing Potential 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP: 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s medical records, 
medical examination, or medical history interview. 
• Premenarchal  
• Postmenopausal female 
o Females who are postmenopausal (age-related amenorrhea ≥ 12 consecutive months 
and increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have 
undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy 
testing. If necessary to confirm postmenopausal status, an FSH will be drawn at 
Screening. 
o Females on hormone-replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrolment. 
Contraceptive Guidance 
Highly Effective Contraceptive Methods That are User Dependent 
Failure rate of < 1% per year when used consistently and correctly1. 
Combined (estrogen- and progestogen-containing ) 
hormonal contraception associated with inhibition 
of ovulation2: 
Oral 
• Intravaginal 
• Transdermal 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation2: 
 
• Oral 
• Injectable 
Highly Effective Contraceptive Methods That are User Independent 
 Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation2 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 


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 Vasectomised partner (a vasectomised partner is a highly effective contraception method 
provided that the partner is the sole male sexual partner of the WOCBP and the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used.) 
 Sexual abstinence (sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with 
the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant.) 
Note: 
1. Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
2. Hormonal contraception may be susceptible to interaction with the study treatment, which 
may reduce the efficacy of the contraceptive method or susceptible to a clinically relevant 
interaction with contraceptive steroids (observed or suspected). In this cases, two highly 
effective methods of contraception should be utilised during the treatment period and for 
at least 2 months (corresponding to time needed to eliminate study treatment plus 30 days 
for study treatments with genotoxic potential)  after the last dose of study treatment 
 Note: For trastuzumab administration, the subject should use effective contraception during the 
treatment period with trastuzumab and for at least 7 months after the treatment has ended. 
Subjects should not breast feed during and at least for 7 months after treatment with trastuzumab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX III: 
 
 
 
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APPENDIX IV: Recommendations for Management of Toxicities related to MEN1611 
Table 4. Recommendations for the treatment of study drug induced hyperglycemia 
CTCAE v.4.03 Grade of 
Hyperglycaemia  
Consider consultation with a diabetologist and recommend/reinforce on lifestyle changes, i.e. exercise and dietary 
advice. This table provides dose management recommendations. The preferred option for treating MEN1611 
induced hyperglycaemia is metformin. However, in case of intolerance to or unavailability of metformin, 
investigator’s judgement should be exercised and other insulin sensitizers (such as thiazolidinediones or dipeptidyl 
peptidase-4 Inhibitors) can be used. 
Grade 1  
Fasting glucose value > ULN - 160 mg/dL; 
Fasting glucose value > ULN - 8.9 mmol/L. 
For subjects with baseline values between 
> ULN - 140 mg/dL (ULN - 7.7 mmol/L) 
this applies only for values > 140 mg/dL 
(7.7 mmol/L) 
Maintain MEN1611 and counsel subject on lifestyle changes. 
Consider adding or increasing oral anti-diabetic treatment (i.e. metformin) in cooperation with 
diabetologist/endocrinologist. 
Monitor FPG as clinically indicated and at least weekly for 8 weeks, then continue checking as per investigator’s 
judgement. 
Grade 2 
Fasting glucose value > 160 - 250 mg/dL;  
Fasting glucose value > 8.9 - 13.9 mmol/L 
Maintain MEN1611 and counsel subject on lifestyle changes. 
Start or increase oral anti-diabetic treatment i.e. metformin) in cooperation with diabetologist/endocrinologist. 
If FPG level is still increasing with maximum tolerated dose of oral-anti-diabetic treatment or persistently > 160 
mg/dL, consider adding an insulin-sensitizer (i.e. pioglitazone). 
Monitor FPG as clinically indicated and at least weekly until FPG resolves to Grade ≤1. 
Continue with anti-diabetic treatment and check at least weekly for 8 weeks, then continue checking at least every 
2 weeks. 


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Table 4. Recommendations for the treatment of study drug induced hyperglycemia 
Grade 3 
Fasting glucose value > 250 - 500 mg/dL; 
Fasting glucose value > 13.9 - 27.8 mmol/L 
Stop MEN1611 treatment until resolved to Grade ≤ 1. 
Treat electrolyte disturbances as clinically appropriate. 
Start or increase anti-diabetic therapy per standard of care in cooperation with diabetologist/endocrinologist. 
Consider adding pioglitazone as outlined for Grade 2; insulin may be used for 1-2 days until hyperglycaemia 
resolves. 
Monitor FPG as clinically indicated and at least twice weekly until FPG resolves to Grade ≤ 1 
If FPG level resolves to Grade ≤ 1, consider resuming MEN1611: 
- At the same dose level, in subjects who were not receiving a previous optimal antidiabetic therapy, 
- At one dose lower, in subjects undergoing an optimal anti-diabetic therapy. 
Continue with anti-diabetic treatment and check FPG at least weekly for 8 weeks, then continue checking at least 
every 2 weeks. 
Grade 4 
Fasting glucose value > 500 mg/dL; 
Fasting glucose value > 27.8 mmol/L 
Omit MEN1611 treatment. 
Initiate or intensify medication with appropriate anti-diabetic treatment (see Grade 3) in cooperation with 
diabetologist/endocrinologist, recheck within 24 hours. 
Treat electrolyte disturbances as clinically appropriate. 
If FPG level resolves to Grade ≤ 1 within 21 days, consider resuming MEN1611: 
- At the same dose level, in subjects who were not receiving a previous optimal anti-diabetic therapy, 
- At one dose lower, in subjects undergoing an optimal anti-diabetic therapy (1st occurrence). 
Permanently discontinue MEN1611: 
- If FPG level does not resolve to Grade ≤ 1 within 21 days  
- Second occurrence of Grade 4 Hyperglycaemia despite an optimal anti-diabetic treatment and previous dose 
reduction 
 


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Table 5. Recommendations for the treatment of study drug induced cutaneous reactions 
CTCAE v4.03 Grade of Cutaneous 
Reactions 
Consultation with a dermatologist is recommended for better assessment and management of MEN1611 induced skin 
toxicity. Dermatologist consultation is mandatory for Grade ≥3 toxicity. 
Grade 1 
Rash covering < 10% BSA with or 
without symptoms (e.g. pruritus, 
burning, tightness) 
Maintain MEN1611 treatment. 
Initiate topical corticosteroid therapy. 
For subjects with symptoms, such as burning or pruritus, add antihistamine to therapy. 
Grade 2 
Rash covering 10 - 30% BSA with or 
without symptoms (e.g., pruritus, 
burning, tightness); limiting 
instrumental activities of daily living 
(ADL); rash covering > 30% BSA with 
or without mild symptoms 
Maintain MEN1611 treatment 
Initiate topical corticosteroid therapy. 
For subjects with symptoms, such as burning or pruritus, add antihistamine to therapy. 
Consider adding systemic corticosteroids to therapy. (If rash resolves to Grade ≤1 within 10 days systemic 
corticosteroid may be discontinued).  
 
Grade 3 
Rash covering > 30% BSA with 
moderate or severe symptoms; limiting 
self-care ADL 
Stop MEN1611 treatment until skin eruption or toxic effect is no longer active but fading (Grade 1)  
Consult dermatologist. 
Initiate topical and systemic corticosteroid therapy. (If rash resolves to ≤ G1 within 10 days systemic corticosteroid 
may be discontinued). 
For subjects with symptoms, such as burning or pruritus, add antihistamine to therapy. 
Re-start MEN1611 dose once rash /skin toxicity is no longer active but fading (Grade 1): at same dose in case of first 
occurrence, at reduced dose level in case of second occurrence. 


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Table 5. Recommendations for the treatment of study drug induced cutaneous reactions 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
Permanently discontinue MEN1611 treatment. 
Consult a dermatologist, ensure documentation by imaging like photographs, and obtain a skin biopsy for central 
assessment. 
Treatment may follow guidelines for Grade 3. 
Additional measures may be taken as per local treatment guidance. 
 
 
 


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Table 6. Recommendations for the treatment of study drug induced diarrhea 
CTCAE v 4.0 Grade of Diarrhoea  
The subject should be appropriately informed of potential study drug-induced diarrhoea and its management. History 
of onset, number of stools and stools composition should be obtained. Other symptoms such as fever, abdominal pain, 
cramps, distension, bloating, nausea, vomiting, dizziness, and weakness should be assessed (i.e., rule out risk for 
sepsis, bowel obstruction, dehydration). Medication and dietary profile should be also obtained to identify any 
diarrheogenic agents or diarrhea-enhancing foods. 
Counsel on dietary modification (drink 8 to 10 large glasses of clear liquids, eat frequent small meals).  
Grade 1 
Increase of <4 stools per day over 
baseline; mild increase in ostomy output 
compared to baseline 
Grade 2 
Increase of 4 - 6 stools per day over 
baseline; moderate increase in ostomy 
output compared to baseline; limiting 
instrumental ADL 
Maintain MEN1611 treatment. 
Intensive management of diarrhea must be instituted at the first sign of abdominal cramping, loose stools or overt 
diarrhea. 
General recommendations:  
- Stop all lactose-containing products, alcohol, laxatives, bulk fiber and stool softeners, and high-osmolar food 
supplements. 
- Drink 8 to 10 large glasses of clear liquids per day and eating frequent small meals (e.g. bananas, rice, apple 
sauce, toast) 
Start loperamide at first sign of loose stools or abdominal cramping: initial administration of 4 mg, then 2 mg every 4 
hrs (maximum of 16 mg/day). 
Diphenoxylate hydrochloride/atropine sulfate may be used in place of loperamide. Do not administer loperamide and 
diphenoxylate hydrochloride/atropine sulfate in conjunction with one another due to the risk of developing paralytic 
ileus. 
In case of persisting Grade-2 diarrhea, if subject does not need hospitalization, consider adding opium tincture or 
dihydrocodeine tartrate tablets/injections (SC or IM). Monitor subjects every 3 (± 1) days to rule out associated 
complications such as dehydration, ileus, hypokalemia, etc. 


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In case of persistent Grade-2 diarrhea despite optimal symptomatic treatment (high dose loperamide and opiates), stop 
all study-treatment, consider hospitalization and employ measures as for Grade 3-4 until diarrhea resolved. 
If diarrhea is resolved, discontinue loperamide and/or other treatment after 12 hours diarrhea-free interval, If 
treatment is stopped for less than 7 days, when diarrhea is resolved restart MEN1611 at the same dose.  
If study treatment has been delayed during 8-14 days, when diarrhea is resolved restart MEN1611 at a reduced dose.  
If treatment has been delayed for 15-21 days, subject may be withdrawn from the study or treated with MEN1611 at a 
reduced dose according to Investigator’s clinical judgment, after receiving the Sponsor’s endorsement.  
Grade 3 
Increase of  ≥7 stools per day over 
baseline; hospitalization indicated; 
severe increase in ostomy output 
compared to baseline; limiting self-care 
ADL 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated. 
Stop all study drug.  
Hospitalize the subject. Complete workup and additional tests: 
- Collect stool separating it from urine 
- Blood 
- Fecal leukocytes (Wright's staining and microscopy)  
- Clostridium difficile toxin 
- Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, Cryptosporidium, Shigella 
and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., possibly Aeromonas, Pleisiomonas (if suspected 
exposure to contaminated water)  
Endoscopic examinations may be considered only if absolutely necessary 
Start or mantain high dose loperamide (initial 4 mg, then 2 mg every 2 hrs). Add opium tincture or dihydrocodeine 
tartrate tablets/injections (SC or IM).  
Start of IV fluids and antibiotics as needed with monitoring of subject’s condition (to rule out dehydration, sepsis, 
ileus, hypokalemia, etc.). Observe subject for response. 
If diarrhea persists after 12-24 hours continue IV fluids and antibiotics as needed and administer SC 
Sandostatin/octreotide (100-500 μg TID).  
Treatment should be continued only when diarrhea resolved. If treatment has been delayed for <21 days, restart 
MEN1611 at a reduced dose. 


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Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid 
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in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer 
(BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 
2017 Jul;18(7):904-916. 
25. Leo AD, Ciruelos E, Janni W, et al. BELLE-3: A Phase III study of the pan-
phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib (BKM120) with fulvestrant in 
postmenopausal women with HR+/HER2– locally advanced/metastatic breast cancer (BC) 
pretreated with aromatase inhibitors (AIs) and refractory to mTOR inhibitor (mTORi)-based 
treatment. J Clin Oncol. 2015 33:15_suppl, TPS626-TPS626. 
26. André F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-
resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, 
placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(6):580–591. 


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27. Slamon DJ, Hurvitz SA, Chen D, et al. Predictive biomarkers of everolimus efficacy in 
HER2+ advanced breast cancer: combined exploratory analysis from BOLERO-1 and 
BOLERO-3. J Clin Oncol. 2015;33 Suppl:512. 
28. Yang SX, Polley E, Lipkowitz S. New insights on PI3K/AKT pathway alterations and 
clinical outcomes in breast cancer. Cancer Treat Rev. 2016 Apr; 45:87-96. 
29. Di Leo A, Curigliano G, Diéras V, et al. New approaches for improving outcomes in breast 
cancer in Europe. Breast. 2015 Aug;24(4):321-30. 
30. Juric D, Krop I, Ramanathan RK. Phase I Dose Escalation Study of Taselisib (GDC-0032), 
an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumours. Cancer Discov. 2017 
Jul;7(7):704-715. 
31. Rugo HS, Andre F, Rubovszky G, et al. A Phase 3 study of alpelisib (ALP) plus fulvestrant 
(FUL) in men and postmenopausal women with hormone receptor-positive 
(HR-POSITIVE), human epidermal growth factor receptor 2-negative (HER2-) ABC 
progressing on or after aromatase inhibitor (AI) therapy: SOLAR-1. J Clin Oncol. 2017 
35:15_suppl, TPS1111-TPS1111. 
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for First-in-human Clinical Trials with Investigational Medicinal Products 
(EMEA/CHMP/SWP/28367/07 Rev. 1). Available from: 
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College of American Pathologists guideline recommendations for immunohistochemical 
testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med. 
2010;134:907–922 
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tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228- 

SAP_001.pdf: 
STUDY CODE: MEN1611-01
STATISTICAL ANALYSIS PLAN (SAP) 
OPEN-LABEL, MULTICENTRE, PHASE IB DOSE-ESCALATION STUDY 
OF MEN1611, A PI3K INHIBITOR COMBINED WITH TRASTUZUMAB ± 
FULVESTRANT, IN SUBJECTS WITH PIK3CA MUTATED HER2-POSITIVE 
LOCALLY RECURRENT UNRESECTABLE (ADVANCED) OR 
METASTATIC (A/M) BREAST CANCER PROGRESSED TO ANTI-HER2 
BASED THERAPY 
Sponsor: 
Menarini 
Ricerche 
S.p.A, 
Clinical 
Research 
Department, Via Sette Santi, 1; 50131 Florence, Italy 
EudraCT-No.: 
2017-004631-36 
Investigational medicinal Product:
MEN1611 oral capsules 
Development Phase: 
Phase 1b 
Indication: 
Advanced or Metastatic Breast Cancer 
Date of First Patient In:  
23OCT2018 
Date of Last Patient Out: 
NA 
SAP Version and date  
Protocol Version and date 
1.0 11AUG2023 
5.0 03MAR2022 
STATEMENT OF CONFIDENTIALITY
The study is conducted according to the protocol and in compliance with International Conference of Harmonisation - 
Good Clinical Practice (ICH-GCP), the Declaration of Helsinki (and subsequent amendments) and the applicable 
regulatory requirements. 
This document contains confidential information of Menarini Group. Do not copy or distribute without written 
permission from the sponsor. 
NCT #: NCT03767335


Study code: MEN1611-01 
 Statistical Analysis Plan (SAP) 
EudraCT no.: 2017-004631-36 
 Version n.1.0, 11AUG2023 
MR-GCS-DMST-210.A_Template – Statistical Analysis Plan 
 Version 1, Eff. date 31-March-2022 
 Page 2 of 49 
SIGNATURE PAGE 
I have read this report and confirm that to the best of my knowledge it accurately describes the planned 
statistical analyses of the study. 
Author 
Signature 
Date 
Reviewer 
06SEP2023 
Signature 
Date 
Approver 
Signature 
Date 
06Sep2023
06Sep2023


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
EudraCT no.: 2017-004631-36                             Version n.1.0, 11AUG2023 
 
 
MR-GCS-DMST-210.A_Template – Statistical Analysis Plan                                                 Version 1, Eff. date 31-March-2022  
 
 
 
 
 
 
    
 
 
 
 
 
     Page 3 of 49 
 
 
Table of contents 
 
1. 
Version History .................................................................................................................................................. 5 
2. 
List of abbreviations........................................................................................................................................... 6 
3. 
Introduction ...................................................................................................................................................... 10 
3.1. 
Changes from study protocol ...................................................................................................................... 10 
4. 
Study overview ................................................................................................................................................ 11 
4.1. 
Study objectives .......................................................................................................................................... 11 
5. 
Investigational plan .......................................................................................................................................... 12 
5.1. 
Study configuration and structure ................................................................................................................ 13 
5.2. 
Schematic study design .............................................................................................................................. 15 
5.3. 
Study flow chart ........................................................................................................................................... 16 
5.4. 
Study Endpoints .......................................................................................................................................... 21 
5.4.1. 
Primary endpoints.................................................................................................................................... 21 
5.4.2. 
Secondary endpoints ............................................................................................................................... 21 
5.4.3. 
 .............................................................................................................................. 22 
5.4.4. 
Safety endpoints ...................................................................................................................................... 22 
5.4.5. 
PK endpoints ........................................................................................................................................... 23 
6. 
General specifications ..................................................................................................................................... 24 
6.1. 
Data validation ............................................................................................................................................. 24 
6.2. 
Computer system and software used .......................................................................................................... 24 
6.3. 
Coding systems ........................................................................................................................................... 24 
6.3.1. 
Clinical Terms .......................................................................................................................................... 24 
6.3.2. 
Drugs ....................................................................................................................................................... 24 
6.3.3. 
Classification criteria................................................................................................................................ 24 
6.4. 
Report type, language, format ..................................................................................................................... 24 
6.5. 
Standard Operating Procedures (SOPs) to be followed ............................................................................. 25 
6.6. 
Data Transfer Agreements .......................................................................................................................... 25 
7. 
Definitions and general methodology .............................................................................................................. 26 
7.1. 
Data quality assurance ................................................................................................................................ 26 
7.2. 
General considerations and key definitions ................................................................................................ 27 
7.2.1. 
General considerations ........................................................................................................................... 27 
7.2.2. 
Key definitions ......................................................................................................................................... 27 
7.3. 
Analysis populations .................................................................................................................................... 31 
7.4. 
On study and pre-study closure activities ................................................................................................... 31 
7.4.1. 
Data monitoring ....................................................................................................................................... 31 
7.4.2. 
Protocol Deviations and Data Review Meeting ....................................................................................... 32 
8. 
Determination of sample size .......................................................................................................................... 33 
9. 
Randomization Methodology ........................................................................................................................... 33 
10. 
Stopping Rules and Blinding ....................................................................................................................... 33 
10.1. Stopping Rules ............................................................................................................................................ 33 
10.2. Blinding ........................................................................................................................................................ 33 
11. 
Statistical analysis and methods ................................................................................................................. 33 
11.1. Multiplicity adjustment ................................................................................................................................. 33 
11.2. Descriptive statistics .................................................................................................................................... 34 
11.3. Data imputation ........................................................................................................................................... 34 
11.4. Patient disposition and Baseline tables ....................................................................................................... 35 
11.5. Safety analysis ............................................................................................................................................ 37 
11.5.1. 
Safety assessments ................................................................................................................................ 37 
11.5.2. 
Treatment exposure and compliance ...................................................................................................... 37 
11.5.3. 
Adverse Events ....................................................................................................................................... 38 
11.5.4. 
Vital Signs ................................................................................................................................................ 40 


 
 
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11.5.5. 
Physical Examination .............................................................................................................................. 40 
11.5.6. 
12-ECG, ECHO or MUGA, ECOG performance status .......................................................................... 40 
11.5.7. 
Safety laboratory tests ............................................................................................................................. 41 
11.5.8. 
Pregnancy test ......................................................................................................................................... 41 
11.5.9. 
Additional Safety Analyses ...................................................................................................................... 41 
12. 
Efficacy evaluations ..................................................................................................................................... 41 
12.1. Efficacy analysis .......................................................................................................................................... 42 
12.2. Subgroup analyses ...................................................................................................................................... 44 
12.3. Pharmacokinetic analysis ............................................................................................................................ 44 
13. 
Tables, listings and figures .......................................................................................................................... 44 
13.1. Statistical Analysis Report ........................................................................................................................... 44 
13.2. Index of TLFs ............................................................................................................................................... 45 
13.2.1. 
Tables ...................................................................................................................................................... 45 
13.2.2. 
Listings .................................................................................................................................................... 48 
13.2.3. 
Figures ..................................................................................................................................................... 49 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1. Version History 
 
Version Date 
Author 
Description for Revision 
1.0 
DDMMMYYY 
Name Surname 
This is the first final version of this document 
2.0 
11AUG2023 
 
Template update 
 
 


 
 
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2. List of abbreviations  
ADaM 
Analysis Data Model 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ANC  
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area Under Curve 
b.i.d. 
bis in die (twice daily) 
BIRC 
Blinded Independent Review Committee 
BLLOQ 
Below the Lower Limit of Quantification 
BP 
Blood Pressure 
BR 
Breath Rate 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CDB 
Clinical Database 
CDISC 
Clinical Data Interchange Standards Consortium 
CHF 
Congestive Heart Failure 
CR 
Complete Response 
CRC 
Cohort Review Committee 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CSP 
Clinical Study Protocol 
ct 
Circulating tumour 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLS 
Clinical Tumor Lysis Syndrome 
CYP 
Cytochromes  
DLT 
Dose Limiting Toxicity 
DM 
Data Management 


 
 
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DRM 
Data Review Meeting 
DSM 
Drug Safety Manager 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
GM 
Geometric Mean 
HBcAg 
Hepatitis B core Antigen 
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human  Immunodeficiency Virus 
HER2 
Human Epidermal growth factor Receptor 2 
HM 
Haematologic Malignancies 
HR 
Heart Rate 
HR 
Hormone Receptor 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
iDSMB 
Independent Data Safety Monitoring Board 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDH 
Lactate Dehydrogenase 
LLT 
Lowest Level Term 
LOCF 
Last observation carry forward 


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LTLS 
Laboratory Tumor Lysis Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
MRI 
Magnetic Resonance Imaging 
NSADR 
Non-serious Adverse Drug Reaction 
NSAE 
Non-serious Adverse Event 
OS 
Overall Survival 
PFS 
Progression free Survival 
PI3K 
Phosphoinositide 3-kinase 
PIK3CA 
Phosphatidylinositol 3-kinase catalytic alpha 
PK 
Pharmacokinetics 
PP 
Per-protocol 
PR 
Partial Response 
PRP 
Platelet Rich Plasma 
PS 
Performance Status 
PT 
Preferred Term 
QA 
Quality Assurance 
q.d.
quaque die (every day) 
RBC 
Red Blood Cells 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase 2 dose 
RO 
Receptor Occupancy 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Statistical Analysis Report 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
sUA 
serum Uric Acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


 
 
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TEAE 
Treatment Emergent Adverse Event 
TLS 
Tumor Lysis Syndrome 
TMF 
Trial Master File 
UA 
Uric Acid 
UGT 
Uridine Diphosphate Glucuronosyltransferase  
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organization 


 
 
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3. Introduction 
This document is aimed to describe the statistical analysis methods, in alignment with the study 
protocol MEN1611-01 Final Version 5.0 dated 03 March 2022, and following the internal SOP 
MR-CR-136/01. It follows the principles of the guidelines ICH Topic E3 and ICH Topic E9 
regarding the structure and content of clinical study reports and regarding statistical principles for 
clinical trials. 
The sponsor of the study is Menarini Ricerche S.p.A. 
Section 4 provides a study overview and presents the study objectives. In Section 5 the study 
design and the endpoints are described in a detailed way and also the study flow chart, taken 
from the Clinical Study Protocol v3.0, is reported. Section 6 presents some general specifications 
for the data validation, the computer systems, software and coding systems used. All definitions 
and the general methodology for the study activities are reported in Sections 7 through 10, while 
the analyses and summaries that will be produced and detailed specifications on the statistical 
methodology are presented in Sections 11 and 12. Section 13 provides the complete index of 
tables, listings and figures for the Statistical Analysis Report that will be generated at the end of 
the study. 
3.1. Changes from study protocol 
The PK analysis of this study will be performed by an external vendor and it will not be part of this 
SAP. 
All the other analyses reported in this document are as specified in the protocol and subsequent 
amendments, no major changes from the protocol-planned primary analysis have been performed. 


 
 
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4. Study overview 
MEN1611 is a potent and selective Class I PI3K inhibitor with a novel structure; in particular it has 
potent inhibitory activities against Class I PI3kα. The MEN1611 drug product is a hard 
hypromellose capsule for oral administration, one capsule contains 16 mg MEN1611 free base. 
This study is designed as an open-label, multicentre, Dose-escalation and Cohort-expansion, 
Phase Ib study to be conducted in approximately 50 European, Russian and US sites. 
Subjects with HER2-positive a/m breast cancer harbouring PIK3CA mutation and pre-treated with 
at least two lines of anti-HER2 based therapy will be enrolled.   
The study is aimed to determine the MTD and RP2D of MEN1611 when administered in 
combination with trastuzumab ± fulvestrant to aforementioned subjects according with HR status 
and menopausal status. 
4.1. Study objectives 
1.1. 
Primary objective(s) 
The primary objective of the study is to determine the MTD and RP2D of MEN1611 when 
administered orally in combination with trastuzumab ± fulvestrant to adult subjects with PIK3CA 
mutated HER2-positive breast cancer, pre-treated with at least 2 anti-HER2 based therapy. 
1.2. 
Secondary objective(s) 
The secondary objectives of the study are the following: 
• To assess the safety and tolerability of MEN1611 in combination with trastuzumab ± 
fulvestrant. 
• To assess the preliminary anti-tumour activity and clinical efficacy of MEN1611 in 
combination with trastuzumab ± fulvestrant. 
• To assess the PK profile of MEN1611 when given in combination with trastuzumab ± 
fulvestrant. 
1.3. 


 
 
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5. Investigational plan 
An overview of the Clinical Study Protocol is provided in this Section. 


 
 
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5.1. Study configuration and structure 
The study design is in agreement with the current regulatory EMA guidelines regarding the 
evaluation of anticancer medicinal products in man [EMA, Guideline on evaluation of anticancer 
medicinal products in man, Rev.4 – December 2012;EMA/CHMP/205/95 under revision (Rev.5)]. 
Starting from Protocol version 4.0, trastuzumab has to be administered every 3-weeks for new 
patients to be included in the study at the time of this protocol is in force (patients on 3-weekly 
trastuzumab administration schedule), therefore cycle duration is reduced to 21 days. Patients 
already included in the study, continue with the weekly trastuzumab administration schedule and 
28-day Treatment cycles. 
The study consists of 2 sequential steps: dose-escalation and cohort expansion phase. 
At the time of the implementation of the Protocol Version 4.0, Step 1 has been completed. 
Step 1 (Dose-escalation Phase): 
A 3-cohort, ascending-dose (16 mg, 32 mg and 48 mg, BID) design identified the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of MEN1611 in combination 
with trastuzumab ± fulvestrant. MEN1611 was given in combination with weekly intravenous 
infusion of trastuzumab ± 4-week intramuscular (IM) injection of fulvestrant until objective disease 
progression was documented or another criterion for discontinuation was met. 
The number of subjects per cohort was assigned according to a 3 + 3 classical design, e.g. a 
minimum of 3 subjects in each dose cohort and if 1 of the first 3 subjects experiences a dose 
limiting toxicity (DLT), 3 additional subjects were to be assigned to the same dose level. 
The MTD is defined as the highest dose level at which no more than 1 of 6 subjects experience a 
DLT during the DLT assessment window (28 days after the first MEN1611 administration). 
RP2D is defined as MTD or the maximum dose judged to be tolerable by the SRC. 
DLT, defined as any of the following ADRs (ADR is defined as any adverse event suspected by 
the Investigator and/or the Sponsor to be related to MEN1611 when given in combination with 
trastuzumab ± fulvestrant) related to the combination regimens or to MEN1611 alone and 
unrelated to the subjects’ underlying disease or concomitant medication occurring during the DLT 
assessment period (28 days after the first MEN1611 administration): 
• 
Any grade 3 (lasting > 7 days) or grade 4 increase in aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase (ALP). In subjects with hepatic 
metastases, AST or ALT >8x ULN or AST or ALT >5x ULN for ≥14 days is considered a 
DLT. In subjects with grade 2 AST, ALT, or ALP levels at baseline, an elevation to ≥ 10 × 
upper limit of normal (ULN) is considered a DLT. 
• 
Any grade 3 (lasting > 7 days), or grade 4 if asymptomatic, increase in amylase and/or 
lipase. 


 
 
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• 
Any grade ≥ 3 cardiac toxicity or new segmental wall-motion abnormalities. 
• 
Any grade ≥ 3 non-hematologic toxicity (lasting > 7 days) with the following exceptions: 
o Nausea. 
o Vomiting. 
o Diarrhoea. 
o Skin rash. 
o Hyperglycaemia. 
Note: Nausea, vomiting and diarrhoea will be considered a DLT if they are grade ≥ 3 for more 
than 72 hours with adequate antiemetic and other supportive care. Skin rash and hyperglycaemia 
will be considered DLT if they reach grade ≥3 despite adequate treatment as per the institution 
guidelines. 
• 
No recovery from a non-DLT relative to the above exceptions of grade ≥ 3 toxicity to 
grade ≤ 2 for more than 14 days. 
• 
Febrile neutropenia (ANC < 1.0 × 109/L and fever ≥ 38.5°C) and/or documented infection 
with ANC < 1.0 × 109/L. 
• 
NCI CTCAE v4.03 grade 4 neutropenia (ANC < 0.5 × 109/L) lasting ≥ 7 days. 
• 
NCI CTCAE v4.03 grade ≥ 3 thrombocytopenia (platelets < 50 × 109/L) with bleeding, 
lasting ≥ 7 days and grade 4 thrombocytopenia (platelets < 25 × 109/L) associated with or 
without non-traumatic bleeding, or bleeding requiring platelet transfusion. 
• 
Grade ≥3 fatigue lasting > 1 week. 
• 
Grade ≥3 electrolyte abnormalities that last more than 72 hours, unless the subject has 
clinical symptoms, in which case all grade ≥3 abnormalities regardless of duration should 
count as a DLT. 
• 
Any NCI CTCAE v4.03 grade 4 (life-threatening consequences; urgent intervention 
indicated) anaemia lasting ≥ 7 days. 
• 
Any death not clearly due to the underlying disease or extraneous causes. 
• 
Final effective dose of MEN1611 is administered < 80% and/or trastuzumab and/or 
fulvestrant are administered < 100% of the total scheduled dose for safety reason. 
• 
Any other study treatment-related toxicity considered significant enough to be qualified as 
DLT in the opinion of any of the Investigators. 
Step 2 (Cohort-expansion Phase): 


 
 
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The RP2D will be confirmed in additional male and female subjects with PIK3CA mutated/HER2+ 
a/m breast cancer, in order to achieve a total of 30 subjects in each of the following treatment 
cohorts exposed to the MTD: 
• 
HR-negative men and women, and HR-positive men and premenopausal women will be 
enrolled to receive MEN1611 + trastuzumab. 
• 
HR-positive postmenopausal women will be enrolled to receive MEN1611 + trastuzumab 
+ fulvestrant. 
Step 2 will explore the preliminary anti-tumour activity of MEN1611 combined with trastuzumab ± 
fulvestrant with further assessment of their safety and tolerability. 
The overall study duration will depend on the completion of the escalating dose levels/cohorts, 
the number of subjects to be treated per each dose-cohort, and the completion of the expansion 
cohort up to a total of 30 subjects in each of two treatment cohorts exposed to the MTD.  
All subjects pre-screened for the PIK3CA mutation will undergo a maximum 4-week Screening 
Period. If the complete assessment of the eligibility criteria is available within 3 days from the end 
of the Screening Period, the subject’s eligibility must be confirmed by the Medical Monitor. 
Screen failures can be re-screened upon Medical Monitor’s approval. 
Individual study duration will depend on the duration of the study treatment which continues up to 
disease progression or study discontinuation for other reasons.  
The End of Study Visit will be performed 4 weeks (± 7 days) after the last dose of MEN1611 or at 
the time of Study Withdrawal. 
Unscheduled assessments showing disease progression and leading to subject’s withdrawal can 
replace the End of Study Visit provided that all assessment/procedures scheduled for this visit 
are completed.  
After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status 
according to local practice (a visit or a telephone call) every 12 weeks ± 7 days up to the End of 
Study. 
The study ends with the End of Study Visit of the last subject who discontinues the study 
treatment.  
After End of Study, subjects who are benefiting from the study treatment without disease 
progression can continue to take MEN1611 (in combination with trastuzumab ± fulvestrant) as 
per Investigator decision... 
5.2.  Schematic study design 
A schematic study design for the dose escalation and cohort expansion phase is reported 
below: 


 
 
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DLT = dose-limiting toxicity, HER2+ = human epidermal growth factor receptor-2-positive, HR = 
hormone 
receptor, 
PI3K 
= 
Phosphatidylinositol/phosphoinositide 
3-kinase, 
RP2D 
= 
recommended Phase 2 dose, SRC = Safety Review Committee. 
5.3. Study flow chart 
The study flow chart, taken from Protocol version 5.0, for patients on 3-weekly trastuzumab 
administration schedule is reported. 
 
 
 


 
 
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AE = adverse event, BID = twice daily, CT = computed tomography, ct = circulating tumour, CTC = circulating tumour cell, ECG = electrocardiogram, ECOG PS = 
Eastern 
Cooperative Oncology Group performance status, DNA = deoxyribonucleic acid, FFPE = formalin-fixed paraffin-embedded, HBcAg = hepatitis B core antigen, HbsAg = 
hepatitis 
B surface antigen, HBV = hepatitis B virus, HCG = human chorionic gonadotropin, HCV = hepatitis C virus, HIV = human immunodeficiency virus, HR = hormone 
receptor, IM = intramuscular, MRI = magnetic resonance imaging, MUGA = multi-gated acquisition, PD = pharmacodynamic, PIK3CA = Phosphatidylinositol 3-kinase, 
catalytic, alpha 
polypeptide gene, PK = pharmacokinetic, PRP = platelet-rich plasma, RECIST = Response Evaluation Criteria in Solid Tumours, RNA = ribonucleic acid 
a. 
No time limits. The pre-screening will start as soon as the site is activated. 
b. 
All assessments will be performed within 48 hours prior to administration of the study treatment, unless otherwise indicated. 
c. 
End of Study Visit will be performed 4 weeks (± 7 days) after the last administered dose of MEN1611. 
d. 
12 lead ECG will be performed at screening, at Cycle 1 Day 1 and Cycle 2 Day 1 (one pre-dose and one 2 hours post first daily MEN1611 dose administration) and 
then every 3 weeks prior trastuzumab administration. ECG traces will be collected for retrospective central radiological evaluation by a blinded independent review 
committee. 
e. 
Echocardiography or MUGA will be performed at screening, on Day 1 of every third cycle and at the End of Study visit only if not performed within the previous 14 
days. 
f. 
Tumour assessment will be performed using RECIST version 1.1 with CT scan or MRI according the schedule below. Imaging data will be also collected for 
retrospective central radiological evaluation by a blinded independent review committee. 
- 
Screening Visit: tumour assessment performed for subjects with measurable disease. 
- 
Cycle 1 Day 1: performed ONLY if the last assessment is older than 6 weeks. 
- 
From Cycle 1 Day 1 onwards: to be performed every 8 weeks (within a window of - 7 days). 
- 
End of Study Visit: performed only if the last assessment is older than 8 weeks. 
g. 
Optional new tumour biopsy will be performed upon subject’s consent and centrally analysed for PD during the screening visit. If performed at screening it will be 
repeated on Cycle 3 Day 15 and centrally analysed for PD. 


 
 
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h. 
Starting from Cycle 1 Day 1, IV Trastuzumab 6 mg/kg will be administered every 3 weeks. On Cycle 1 Day 1, alternatively a loading IV dose of 8 mg/kg could be 
administered if considered appropriate by the Investigator. 
i. 
Fulvestrant 500 mg IM injection will be administered to HR‑positive postmenopausal subjects every 4 weeks from Cycle 1 Day 1; an additional dose will be   
administered on Day 15 of Cycle 1 if the subject was not under fulvestrant treatment prior Cycle 1 Day 1. 
j. 
After Cycle 5 Day 1, AEs/concomitant medication will be recorded weekly by telephone call. 
k. 
After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status according to local practice (a visit or a telephone call) every 12 
weeks ±7 days up to a period of 6 months after the first treatment administration to the last subject. 
 
 
Below are reported also the blood and urine samples, PK blood samples, PD hair follicle and platelet-rich plasma 
samples flow charts: 
 
Blood and urine samples flow chart 
 
 
ct = circulating tumour, CTC = circulating tumour cells, DNA = deoxyribonucleic acid, HbA1c = glycated haemoglobin, HBcAg = hepatitis B core antigen, HbsAg = 
hepatitis B surface antigen, HBV = hepatitis B virus, HCG = human chorionic gonadotropin, HCV = hepatitis C virus, HIV = human immunodeficiency virus, PD = 
pharmacodynamic, PK = pharmacokinetic, PRP = platelet-rich plasma, RNA = ribonucleic acid 
a. 
No time limits. The pre-screening will start as soon as the site is activated. 
b. 
All assessments will be performed within 48 hours prior to administration of the study treatment, unless otherwise indicated. 
c. 
End of Study Visit to be performed 4 weeks (± 7 days) after last administered dose of MEN1611. 
d. 
After the End of Study Visit, all subjects evaluable for efficacy will be followed for survival status according to local practice (a visit or a telephone call) every 12 
weeks ±7 days up to a period of 6 months after first treatment administration to the last subject. 
e. 
Blood safety lab tests (haematology, coagulation, chemistry) will be performed in fasting condition, weekly up to Cycle 5 Day 1 and every three weeks afterwards 
(Day 1 of each Cycle). 
f. 
Blood safety lab tests including HbA1c analysis. 
g. 
There is no need to repeat these tests in case they have been performed within 3 months prior to Screening Period in the context of the standard subject’s management. 
h. 
ctDNA and CTC blood sampling only at Day 8 of Cycle 2 and Day 15 of Cycle 3. 
i. 
ctDNA and CTC blood sampling at Day 1 of Cycle 5 and then every 2 cycles. 
 
 
 


 
 
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5.4.       Study Endpoints 
5.4.1. Primary endpoints 
Step 1 (Dose-escalation Phase) 
• 
Identification of MTD, defined as the highest dose level at which no more than 1 of 6 
subjects experience a DLT during the DLT assessment window (28 days after first 
MEN1611 administration). 
• 
Identification of DLT (see DLT definition given in Section 2.1). 
Step 2 (Cohort-expansion Phase) 
• 
Confirmation of RP2D, defined as MTD or the maximum dose judged to be tolerable. 
5.4.2. Secondary endpoints 
• 
Response Rate defined according to RECIST v1.1 as per local radiology 
assessments and centralised blinded independent reading on CT scan or MRI of the 
chest and abdomen (including pelvis and adrenal glands). Any other areas of disease 
involvement should be additionally investigated based on signs and symptoms of the 
individual subject. 
For the Baseline assessment, CT scan or MRI should be performed no more than 6 
weeks before the start of study treatment. Follow-up assessment will be performed 
every 8 weeks during study treatment starting from Day 1 Cycle 1(within a window of 
- 7 days) until objective disease progression as defined by RECIST v1.1 or at the End 
of Study Visit. Any other site at which a new disease is suspected should be  
appropriately imaged. If an unscheduled assessment is performed and the disease 
has not progressed, subsequent assessments should be performed at their 
scheduled visits. 
• 
Disease Control Rate (DCR), defined as the percentage of subjects whose disease 
shrinks or remains stable over a certain time period. DCR is the sum of the complete 
response (CR), partial response (PR) and stable disease (SD) rates.  
• 
Duration of Response, defined as the number of days between the first occurrence of 
a BOR of  PR, CR or SD, to the date on which the disease has been shown to 
progress following treatment. Subjects, with a previous response, who do not show a 
relapse or die without recording a relapse are censored at their last available relapse-
free tumor assessment date. Subjects with only one tumor assessment after baseline 
showing a PD, are not included in the calculation. 


 
 
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• 
Progression Free Survival (PFS), defined as the number of days between the first 
study treatment administration to the date of first documented disease progression, 
relapse or death from any cause. Responding subjects and subjects who are lost to 
follow-up are censored at their last tumour assessment date. 
• 
Overall Survival (OS), defined as the number of days between the first study 
treatment administration and death from any cause. Patients still alive, that have 
withdrawn the study, are censored using the latest among end of study and follow-up 
dates. Drop-out patients are considered censored and the last available date in which 
the subject is known to be alive will be considered. 
Note: all secondary endpoints related to tumour assessment will be evaluated 
considering both local and central radiology assessments 
5.4.3. 
 
5.4.4. Safety endpoints 


 
 
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The Safety endpoints for this study are: 
• 
Incidence, intensity, CTCAE v4.03 grading, seriousness and treatment-causality of 
TEAEs. 
• 
Frequency of clinically significant abnormalities in physical examination, safety 
laboratory tests, urinalysis, vital signs, ECHO or MUGA scan and local 12-lead ECG 
5.4.5. PK endpoints 
The following PK variables will be assessed:  
• 
Maximum observed plasma concentration (Cmax) 
• 
Time to Cmax (Tmax) 
• 
Last quantifiable plasma concentration value (Clast) 
• 
Time to Clast (tlast) 
• 
Pre-dose plasma concentration (Ctrough) 
• 
Apparent terminal elimination rate constant (ke) 
• 
Terminal plasma half-life (t1/2) 
• 
Area under the plasma concentration-time curve from time zero (pre-dose) to the time 
of the last quantifiable concentration (AUC[0-t]) 
• 
Area under the plasma concentration-time curve from time zero to infinity (AUC(0-∞)) 
• 
Percentage of  AUC(0-∞) obtained by extrapolation (%AUCex) 
• 
Apparent systemic clearance (CL/F) 
• 
Apparent volume of distribution at steady state (Vss/F) 
• 
Volume of distribution based on terminal phase (Vd/F) 
PK parameters will be calculated after single and repeated dose administration.  


 
 
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6. General specifications 
6.1. Data validation 
Medidata Classic Rave ® 2021.1.4 will be used, as Electronic Data Capture system for data 
entry, by site personnel and for data cleaning and data locking by the Menarini Data 
Management team. 
The eCRF data are elaborated to create the SDTM and ADaM CDISC standard datasets. 
6.2. Computer system and software used 
The software used for all summary statistics and statistical analyses will be SAS® 9.04.01 and 
SAS® Studio version 3.8 or higher (SAS Institute, Inc.). All tables and listings will be produced 
using PROC REPORT or procedure specific output displays using output delivery system 
(ODS). The summary tables and listings will use SAS monospace font of size 6. The default 
page type will be A4 and the default page orientation will be landscape. 
Pharmacokinetic parameters will be derived from the individual plasma concentration-time curve 
for MEN1611 using non-compartmental methods with Phoenix® WinNonlin® software, version 
6.4 or higher (Pharsight Corp., Mountain View, California). 
6.3. Coding systems 
6.3.1. Clinical Terms 
Concomitant diseases, medical procedures, and Adverse Events will be coded with MedDRA 
version 24.1 (or newer if available). 
6.3.2. Drugs 
Drugs will be coded with WHO (ATC coding system) Drug version Sep-2020 (or newer if 
available). 
6.3.3. Classification criteria 
Adverse Events will be graded for severity using the classifications of NCI CTCAE version 4.03.  
6.4. Report type, language, format 
The statistical output will be in pdf format and presented in English language. 
The following criteria will be used: 


 
 
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• 
Dates will be presented with the DDMMMYYYY format. 
• 
Counts and percentages:  
 
<group 1>    XX (XX.X%) 
Note: for Adverse Events tables percentages will be displayed with two decimal 
places. 
• 
Descriptive statistics: 
  
                                               N 
            XX  
 
 
 
 
 
Mean  
XX.XX 
 
 
 
 
 
Median 
XX.XX             
 
 
 
 
 
SD 
 
XX.XXX 
 
 
 
 
 
Minimum 
XX.X 
 
 
 
 
 
Maximum 
XX.X 
In general, the following rule will be applied for decimal place: 
• 
Minimum, maximum: one decimal place 
• 
Arithmetic mean and  median: one more decimal than minimum/maximum 
• 
SD: one more decimal than arithmetic mean/median 
• 
N: no decimal 
Character will be left aligned. 
6.5. Standard Operating Procedures (SOPs) to be followed 
1Code 
Title 
MR-GCS-DMST-210_SOP 
Statistical Analysis Plan (SAP) 
MR-GCS-DMST-211_SOP 
Statistical Programs Writing 
MR-GCS-DMST-211.3_WI 
TLF programming 
 
6.6. Data Transfer Agreements 
Pharmacokinetics data 
 
 


 
 
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Data Transfer Agreement (DTA) between Clinical Laboratory (PK Department) and Data 
Management & Stats of Menarini Ricerche S.p.A, version 1.0 of  24th January 2019. 
CTC enumeration data 
Data Transfer Agreement (DTA) between European Institute of Oncology (IEO) and Menarini 
Ricerche S.p.A, version 1.0 of 08th August 2018. 
Platelet-rich Plasma (PRP), Hair Follicle and tumor data 
Data Handling Requirements (DHR) between Institute of Cancer Research (ICR) and Menarini 
Ricerche S.p.A, version 1.0 of 03 Aug 2018. 
CtDNA data 
Data Transfer Agreement (DTA) between Sysmex Inostics GmbH and Clinical Sciences Dept of 
Menarini Ricerche S.p.A, version 2.0 07 Feb 2022. 
Tumor Tissue Biopsy 
Data Transmission Requirements between Q2 Solution and Menarini Ricerche v2.0 19 Dec 
2019. 
Central radiological evaluation 
249245 RECIST 1.1 Export Requirements and Technical Specifications by Calix specify that 
tumor state for each non-target lesion at each assessment time point will be determined as 
ABSENT, PRESENT, UNEQUIVOCAL PROGRESSION. The same evaluation is reported as 
Complete Response, Non-CR / Non-PD, Progressive Disease in the eCRF for the local 
assessment. 
7. Definitions and general methodology 
7.1. Data quality assurance  
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with Menarini Ricerche standard procedures.  


 
 
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7.2. General considerations and key definitions 
7.2.1. General considerations 
Study day is defined as the number of days from the date of first dose of study treatment to the 
event/visit date. For dates equal to or later than the first dose of study treatment, study day is 
calculated as follows: 
Study Day = Event or Visit Date – First Dose Date + 1 
For dates prior to the first dose of study treatment, study day is calculated as follows: 
Study Day = Event or Visit Date – First Dose Date 
One (1) month will be considered to be equal to 30.4375 days when calculating durations or 
survival times in months.  
7.2.2. Key definitions 
Baseline  
Baseline is defined as the last available (non-missing) value before or on the date and time of 
first administration of any study treatment (Day 1) for Cycle 1. If the value at Day 1 Visit 1 is 
missing or not done, the value measured during the Screening Visit is considered as baseline 
value. 
Adverse Events (AEs)  
An AE is defined as any untoward medical occurrence in a subject or clinical study subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Treatment-Emergent Adverse Events (TEAEs)  
AEs will be categorized as Treatment- Emergent Adverse Events (TEAE) or Non-TEAE. 
If an AE occurs for the first time or if it worsens in terms of seriousness or severity after the first 
study drug intake (either MEN1611, trastuzumab or fulvestrant or their combination) it will be 
classified as TEAE, otherwise it will be considered as non-TEAE or clinical event. 
Drug Relationship 
The relationship between an AE and study treatments will be judged according to the following 
categories:  
1. Certainly related: The event or laboratory test abnormality (AE) with plausible time 
relationship to the drug intake and it cannot be explained by a concurrent disease or other 


 
 
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drugs. The response to withdrawal of the drug (dechallenge) should be plausible 
(pharmacologically, pathologically). The event must be definitive pharmacologically or 
phenomenologically (i.e., an objective and specific medical disorder or a recognised 
pharmacological phenomenon), using a satisfactory rechallenge procedure if necessary.  
 
2. Probably related: The event or laboratory test abnormality (AE) with reasonable time 
relationship to the drug intake, it is unlikely to be attributed to a concurrent disease or other 
drugs and it follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge (AE reappearance after drug reintroduction) is not required. 
 
3. Possibly related: The event or laboratory test abnormality (AE) with reasonable time 
relation to the drug intake, but it could also be explained by disease or other drug. 
Information on drug withdrawal (dechallenge), may be lacking or unclear. 
 
4. Unassessable/Unclassifiable: The relationship cannot be judged, since the information is 
insufficient or contradictory and data cannot be supplemented or verified. 
 
5. Unlikely related: The event or laboratory test abnormality (AE), with a time to drug intake 
that makes a relationship improbable (but not impossible). Disease or other drugs provide 
plausible explanations. 
 
6. Not Related: The event or laboratory test abnormality (AE), with a time to drug intake with 
an unreasonable relationship and/or non-plausibility and/or in case of the existence of a 
clear alternative explanation. 
In case of disagreement between the Investigator and the Sponsor’s Medical Monitor, the 
more conservative assessment will determine the relationship outcome.  
Adverse Drug Reactions (ADRs)  
Any untoward and unintended responses to an investigational medicinal product related to any 
dose administered. The definition covers also medication errors and uses outside what is 
foreseen in the protocol, including misuse and abuse of the product. 
The definition implies a reasonable possibility of a causal relationship between the event and 
MEN1611, trastuzumab, fulvestrant or any of their combinations. This means that there are 
facts (evidence) or arguments to suggest a causal relationship. 
ADRs are considered all AEs for which the relationship is considered as: 
1. Certainly related 
2. Probably related 
3. Possibly related 
4. Unassessable/Unclassifiable 
 


 
 
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AEs are not considered as ADRs when the relationship is judged as: 
1. Unlikely related 
2. Not related 
If the relationship is not recorded and the Adverse Event is a TEAE, the AE is considered an 
ADR for the analysis purpose.  
Serious Adverse Event (SAE) / Serious Adverse Drug Reaction (SADR)  
Any untoward medical occurrence that at any dose:  
• 
Results in death. 
• 
Is life-threatening.  
• 
In this context “life-threatening” means that the subject was at immediate risk of death 
at the time of the SAE; it does not refer to a SAE that hypothetically might have 
caused death if it was more severe. 
• 
Requires in-subject  hospitalisation or prolongation of existing hospitalisation. 
• 
This means that hospital inpatient admission or prolongation of hospital stay were 
required for the treatment of the SAE or that they occurred as a consequence of the 
event. Visits to a hospital by ambulance or to the emergency room without admission 
will not be regarded as hospitalization unless the event fulfils any other of the 
seriousness criteria. 
• 
Results in persistent or significant disability/incapacity.  
• 
“Persistent or significant disability or incapacity” means a permanent or significant 
and substantial disruption of a person’s ability to carry out routine activities. 
• 
Results in a congenital anomaly/birth defect.  
• 
Is other medically important condition that may jeopardise the patient or may require 
an intervention to prevent one of the outcomes listed above. 
These characteristics/consequences have to be considered at the time the event occurs. 
Any other AE/ADR which is not included in the above definitions will be considered as non-
serious. 
The Investigator should also promptly report all the SAEs to the Sponsor’s Drug Safety 
Manager. 
Note: Hospitalisation lasting less than 24 hours or pre-planned hospitalisation for diagnostic 
procedures or medical intervention, such as chemotherapy administration, shall not qualify as 
SAE. 
Adverse Event (AE) / Adverse Drug Reaction (ADR) Intensity (Severity)  


 
 
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All the Events will be graded for severity using according to the National Cancer Institute 
Common Terminology for Adverse Events version 4.03 (NCI CTCAE v4.03).  
For events not addressed in the NCI CTCAE v4.03 classification, the following grading will 
apply: 
• 
Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• 
Moderate (Grade 2) - Moderate; minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental activity of daily living. 
• 
Severe (Grade 3) - Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care 
activity of daily living. 
• 
Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention indicated.  
• 
Death (Grade 5) - Related to adverse event.  
Adverse Drug Reaction Expectedness 
An ADR is considered unexpected when the nature, intensity, or outcome of which is not 
consistent with the applicable product information provided in the Reference Safety Document 
(MEN1611 Investigator’s Brochure in force, trastuzumab SmPC and fulvestrant SmPC).  
Any other ADR which is not included in the above definition will be considered as expected.  
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any SAE judged by the Investigator or the Sponsor as drug-related and considered as 
unexpected is qualified as a Suspected Unexpected Serious Adverse Reaction (SUSAR). 
SUSARs are subject to expedited reporting as having a “Reasonable Possibility” of 
relationship with the study treatment (MEN1611, trastuzumab, fulvestrant or any of their 
combinations). 


 
 
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7.3. Analysis populations 
The following analysis population will be considered in the statistical analysis: 
• 
DLT population 
DLT population definition is applicable only for patients in the Dose-escalation phase. 
All subjects receiving at least 80% of MEN1611 and 100% of trastuzumab and/or 
fulvestrant during 28 days after the first MEN1611 drug administration with a Safety 
Follow-up of 28 days after the first administration of the study treatment. Any subject 
that has experienced a DLT will also be considered evaluable. Subjects enrolled in 
the Dose-escalation Phase who are not DLT evaluable will be replaced. 
• 
Safety population 
All subjects receiving at least 1 dose of MEN1611. 
• 
Efficacy population 
All eligible subjects who receive at least 8 weeks of any treatment and have at least 1 
disease assessment are to be considered evaluable for efficacy. 
• 
PK population 
All subjects receiving MEN1611and with reliable drug assay data relevant for the PK 
parameter of interest. 
7.4. On study and pre-study closure activities 
7.4.1. Data monitoring 
This study will be monitored in accordance with the ICH Guidelines for GCP.  
Monitoring procedures require that 100% of data are source data verified, particularly focusing 
on informed consents, adherence to inclusion/exclusion criteria, drug accountability, 
documentation of SAEs and the proper recording of efficacy and safety measurements.  
All monitoring activities will be described in detail in the study-specific monitoring plan. 
 
Safety Review Committee 
A Safety Review Committee (SRC) is established consisting of the Principal Investigator(s) and 
the Sponsor’s qualified Medical Representative(s), as well as invited experts (such as 
Statistician and Pharmacokineticist), as appropriate. The SRC is responsible for reviewing and 
evaluating all the available safety data, any DLTs, PK and PD data collected during Step 1 in 
order to confirm the RP2D to be tested in Step 2. 


 
 
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The SRC review meeting is scheduled to take place as soon as possible after the conclusion of 
Cycle 1 of the last DLT evaluable subject, but it may also meet in ad hoc meetings at its 
discretion, as needed in response to events occurring in the study. 
Data will be provided in the approved Data Review Plan. 
Roles and responsibilities of the SRC as well as the meeting schedule are provided in a 
separate SRC Charter.  
 
Blinded Independent Review Committee 
There will be one Blinded Independent Review Committees (BIRCs) with the aim of: 
- Evaluate each subject’s CT (MR scans, applying RECIST 1.1 guideline 
The details of the execution of the blinded reviews are provided in a separate BIRC Charter. 
7.4.2. Protocol Deviations and Data Review Meeting 
Categories of protocol deviations will be defined and will be integrated in the statistical analysis.  
A Data Review Meeting (DRM) will take place at the end of the study in order to evaluate and accept 
the data management report, discuss remaining issues (outstanding queries, unresolved errors) and 
to confirm and approve relevant protocol deviations. After the DRM, the final list of Protocol 
Deviations will be defined. 
The Listing of Protocol Deviation categories will be attached to the SAP after the data review 
meeting, according to the following data structure: 
 
PD 
Category 
number 
Programmed 
by DM 
Importance 
PD 
Category 
PD 
Subcategory 
Description 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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8. Determination of sample size 
A maximum of 18 DLT evaluable subjects are needed to be enrolled in Step 1 (Dose-escalation 
Phase). 
During Step 2 (Cohort-expansion Phase), the RP2D will be confirmed in combination with 
trastuzumab and with trastuzumab and fulvestrant in postmenopausal HR-positive subjects in 
order to achieve a total of 30 subjects (considering also Step 1) in each of the treatment cohorts 
exposed to the MTD. 
Subjects who drop out prior to be evaluable for DLT during the dose-escalation will be replaced. 
Considering a 15% drop-out rate, approximately 80 subjects will be enrolled in the 
study. 
Due to the incidence of PIK3CA mutations and considering the above mentioned drop-out rate, 
and the pre-screening and screening failure rates, around 600 HER2-positive a/m breast cancer 
subjects have to be pre-screened. 
9. Randomization Methodology 
Not Applicable. 
10. Stopping Rules and Blinding 
10.1. Stopping Rules 
No additional rules compared to the ones highlighted in section 5.1. 
10.2. Blinding 
This is an open-label study; thus, study subjects and investigators will not be blinded to treatment 
assignment.  
An independent review committee, blinded to subjects’ treatment assignment, will review 
radiographic images and clinical information collected on-study to determine the endpoints of 
disease response and progression. 
Unblinded safety data will be reviewed at pre-specified intervals by the Safety Review Committee. 
11. Statistical analysis and methods 
11.1. Multiplicity adjustment 
Not Applicable. 


 
 
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11.2. Descriptive statistics 
All study variables (with the exception of PK variables) will be presented by dose cohort and overall 
in Step 1 (Dose Escalation Phase), and by treatment arm and overall in Step 2 (Cohort Expansion 
Phase), using the appropriate descriptive statistics according to the variable nature, unless 
otherwise specified: 
• 
Continuous variables: Number of non-missing observations, arithmetic mean, median, 
standard deviation (SD), minimum and maximum. 
• 
Categorical variables: Number of non-missing observations and column percentages (n, 
%). 
• 
Time to event variables: Number of non-missing observations, number and percentage 
of censored observations, 1st quartile, median and its 95% confidence interval (CI), 3rd 
quartile, Kaplan-Meier survival curves. 
The behaviour over time of study variables will be summarised by dose cohort and overall in Step 
1 (Dose Escalation Phase), and by treatment arm and overall in Step 2 (Cohort Expansion Phase) 
as follows: 
• 
Continuous variables: descriptive statistics for each time point  
• 
Categorical variables: descriptive statistics for each time point  
Correlation among subject’s variables will be evaluated calculating the appropriate correlation 
coefficient with the respective statistical significance level. 
11.3. Data imputation  
In the imputation of missing or partial dates, if the imputed date is after min (death date, cutoff 
date), min (death date, cutoff date) will be used as the imputed date. 
 
If an Adverse Event start date is partially or completely missing, then the following rules will be 
used for the imputation: 
• 
If the start day is missing then the first day of the month will be used.  
• 
If the start day and month are missing then January 01 will be used.  
• 
If the start date is completely missing then the date of first dose will be used.  
• 
If the end date is complete and the imputed start date is after the end date, then the 
start date will be imputed as the end date.  
If an Adverse Event stop date is missing the date will be imputed as follows: 


 
 
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• 
If month and year are present, then impute as the last day of that month 
• 
If only the year is present, impute as December 31 of that year 
• 
If the stop date is entirely missing, assume the event is ongoing 
The imputation rules for CM are the same as the rules for AE. 
Completely or partially missing TA dates will not be imputed. 
• 
In case date of last TA is missing and there are no previous TA dates, then the date 
of first study drug admin will be used 
• 
In case date of last Ta is missing and there are previous TA dates, then the previous 
TA date will be used for censoring 
If in the eCRF the last tumour assessment of a patient, has been entered as an unscheduled 
assessment, for analysis purpose it will be associated to End of Study assessment. 
Other missing values will not be imputed since for every analysis an observed-cases approach will 
be applied. 
11.4. Patient disposition and Baseline tables 
Patient disposition 
The number of patients screened, the number of screening failures, and the number of patients in 
each population (DLT, Safety, Efficacy and PK) will be presented by dose cohort and overall in 
Step 1 (Dose Escalation Phase), and by treatment arm and overall in Step 2 (Cohort Expansion 
Phase), as applicable. In these tables, the percentages will be calculated using the total number of 
patients in the Safety population in the respective cohort/treatment arm as the denominator (when 
appropriate).  
The number and percentage of patients who discontinued the treatment and who withdrawn the 
study, with the respective reasons, will be summarized by cohort and overall in two different tables. 
Demographic and baseline data  
The following demographic, disease and baseline characteristics will be summarized by cohort 
using descriptive statistics (as described in Section 5.2.1) computed on the Safety population: 
1. Age (years) 
2. Ethnicity 
3. Gender 
4. Weight (Kg) 
5. ECOG PS at baseline 
6. HR status 
7. Menopausal status 


 
 
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8. IHC result 
9. FFPE tissue sample type 
10. Tumor Grade 
11. Sites of metastasis  
12. Number of previous cancer treatments 
13. Number of previous metastatic cancer treatments 
14. Duration of the response to last treatment 
Medical History and Procedure History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA ). 
The number of patients with at least one recorded medical history or current medical condition will 
be presented using frequency counts and percentages by System Organ Class (SOC) and 
Preferred Term (PT).  
Analogous table will be produced also for Procedure History. 
The safety population will be used as analysis population for these tables.  
Note: Medical History are those conditions which are not ongoing at the date and time of first 
MEN1611 intake; current medical conditions are the ones ongoing at the date and time of first 
MEN1611 intake. 
Anti-cancer, Prior and/or Concomitant medication 
Anti-cancer, Prior and/or Concomitant medication will be coded using the WHO drug dictionary and 
summarised by PT and by Anatomical Therapeutic Chemical (ATC) category level. 
The safety population will be used as analysis population for these tables.  
Note: Prior medications are those with start and end dates prior to the date and time of first 
MEN1611 intake, concomitant medications are those with start and end dates on or after the date 
and time of first MEN1611 intake, prior and concomitant medications are those with start date prior 
to the date and time of first MEN1611 intake and end date on or after the date and time of first 
MEN1611 intake or still ongoing. 
Prior Radiotherapy 
The number of patients with at least one recorded prior radiotherapy, classified by reason for 
regimen and location of administration, will be presented using frequency counts and percentages. 
The safety population will be used as analysis population.  
Substance use 
The number of smoker/non smoker patients will be presented using frequency counts and 
percentages in a table by cohort. 
Virology 


 
 
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A summary table of Virology results obtained at Screening visit with frequencies and percentages, 
calculated considering the patients who have performed the examination at each visit, by cohort 
will be provided in the TLFs. 
11.5. Safety analysis 
Safety analysis will be performed on the safety population through descriptive statistics during 
each study phase. Summary statistics (N (%) and number of events) will report the incidence of the 
AEs using combinations of the following variables for the descriptive stratification: toxicity grade, 
dose level, relationship to study treatment, System Organ Class and Preferred Term and overall. 
Also AEs summary tables will be created by cohort (Cohort 1, Cohort 2, and Cohort 3+Expansion), 
by treatment combination and overall. 
Counts and percentages will be reported for the results of ECG, laboratory values, vital signs, 
physical examination, all classified as Normal/Abnormal Not Clinically Significant/Abnormal 
Clinically Significant by cohort (dose level) and visit. 
11.5.1. 
Safety assessments 
Safety and tolerability endpoints will be derived from the following measurements/evaluations: 
• 
Incidence, intensity, CTCAE v.4.03 grading, seriousness and treatment-causality of 
TEAEs; 
• 
Frequency of clinically significant abnormalities in: 
o Physical examination and vital signs 
o Safety laboratory tests  
o 12-lead ECG record 
o Urinalysis 
o ECHO or MUGA scan 
11.5.2. 
Treatment exposure and compliance 
For MEN1611: 
• 
cumulative dose (mg) is the sum of the number of capsules taken at each occasion 
multiplied by the strength of each capsule. 
• 
Treatment duration (days) is calculated as (Last dose date – First dose date + 1). 
For trastuzumab: 


 
 
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• 
cumulative dose (mg) is the sum of volumes (mL) administered at each infusion 
multiplied by the amount of trastuzumab contained in the solution (i.e. 21 mg/mL). 
• 
Treatment duration (days) is calculated as (End date of last cycle – First dose date + 
1). 
For fulvestrant: 
• 
cumulative dose (mg) is the sum of number of syringes injected multiplied by the 
capacity of each syringe (i.e. 250 mg). 
• 
Treatment duration (days) is calculated as (End date of last cycle – First dose date + 
1). 
End date of last cycle is the earliest of the following dates: the expected end date of last cycle, date 
of death, date of last known alive, date of subject withdrawal from the study, or the analysis cut-off 
date if subject is known to be alive after analysis cut-off date. 
 
Expected end date of last trastuzumab cycle is calculated as: 
• 
for patients enrolled before Protocol v4.0, expected end date of last cycle is the Date 
of Day 1 of last cycle + 27 days 
• 
for patients enrolled on or after Protocol v4.0, expected end date of last cycle is the 
Date of Day 1 of last cycle + 20 days 
Expected end date of last fulvestrant cycle is calculated as: 
• 
If last dose of fulvestrant was administered on Day 15 of Cycle 1, expected end date 
of last cycle is the last dose date + 13 days 
• 
If last dose of fulvestrant was administered on Day 1 of any cycle, expected end date 
of last cycle is the last dose date + 27 days 
Number of cycles will be determined based on the drug administrations occurred: if at least one 
dose of any treatment is administered during a cycle, that cycle will be taken into account 
11.5.3. 
Adverse Events 
All identified AEs are recorded and described on the appropriate AE page of the eCRF, except for 
those events occurring prior to the screening period, which are recorded on the Medical History 
eCRF page. All Adverse Events recorded in the eCRF will be listed. All AEs summaries will be 
based on the safety population.  
The number and percentage of patients experiencing one or more AEs, as well as the number of 
events, will be summarized in the safety tables by cohort and seriousness. 


 
 
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An overview of AEs will be provided with the number and percentage of patients reporting an event 
by cohort and by treatment group and overall, as well as the number of events,. The summaries 
will be presented for the following categories: 
• 
Any AE 
• 
Any Serious AE 
• 
Any Related AE 
• 
Any Serious and Related AE 
• 
Any AE by Relationship, Outcome, Intensity/Severity (Grade), Pattern 
The number and percentage of patients experiencing one or more TEAEs will be summarized in 
the safety tables by cohort, relationship to study drug, seriousness, intensity/severity and action 
taken. 
An overview of TEAEs will be provided with the number and percentage of patients reporting a 
TEAE by cohort and by treatment group and overall, as well as the number of events,. The 
summaries will be presented for the following categories: 
• 
Any TEAE 
• 
Any Serious TEAE 
• 
Any Related TEAE 
• 
Any Serious and Related TEAE 
• 
Any TEAE by Relationship, Outcome, Intensity/Severity (Grade), Pattern, Action 
Taken 
• 
In addition, within each of the above categories, TEAEs will be further presented as 
follows: 
• 
All TEAEs 
• 
TEAEs by Grade and Grade Category 
• 
TEAEs leading to drug interruption 
• 
TEAEs leading to drug withdrawal 
• 
TEAEs leading to dose modification (i.e. either dose reduction or dose increase) 
• 
TEAEs leading to death 
DLTs will be presented in a dedicated summary table. 
AEs will be considered as related to study treatment if they are judged to be related to MEN1611 or 
to any of its combinations (i.e. MEN1611 + Trastuzumab, MEN1611 + Fulvestrant, MEN1611 + 
Trastuzumab + Fulvestrant). 


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
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The following information will be reported for all AE/TEAE listings: reported term, preferred term 
(PT) and system organ class (SOC), start and end date/time of the event, causality, intensity 
(grade), seriousness, pattern, outcome, action taken and report type (follow-up/initial).   
In the listings, all AEs and their eventual follow-ups will be reported. 
Listings will be produced for all AEs, all TEAEs, DLTs, Serious TEAEs, Related TEAEs, Serious 
Related TEAEs. 
Whenever a patient experiences two or more AEs reported under the same Preferred Term and 
part of the same initial/follow up(s) group, these events will be counted as one. This will apply to all 
the AEs/TEAEs tables, except for those reporting the events stratified by action taken in which the 
TEAEs will be counted individually.  
For the overview tables of AEs/TEAEs the outcome that is shown is obtained taken the last 
outcome among the initial and follow up(s) (if any). 
11.5.4. 
Vital Signs 
Descriptive statistics for Vital Signs results (Systolic and Diastolic Blood Pressure, Heart Rate, 
Height, Respiratory Rate, Temperature, Heart Rate, Weight) by Visit will be provided in the TLFs, 
both in terms of absolute values and change from baseline. 
Also frequencies and percentages for the investigator judgements, calculated considering the 
patients who have performed the examination at each visit, are reported.  
11.5.5. 
Physical Examination 
A summary table of Physical Examination parameters by cohort and visit will be provided in the 
TLFs. Percentages are calculated considering the patients who have performed the examination. 
11.5.6. 
12-ECG, ECHO or MUGA, ECOG performance status 
Summary tables of 12-lead ECG parameters and interpretation, ECHO or MUGA parameters and 
interpretation and ECOG performance status by cohort and visit will be provided in the TLFs, both 
in terms of absolute values and change from baseline.  
In these tables the frequencies and percentages, calculated considering the patients who have 
performed the examination at each visit, are reported. 


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
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11.5.7. 
Safety laboratory tests 
An overall summary table of hematology, biochemistry, coagulation and urinalysis parameters by 
cohort and visit will be provided in the TLFs, both in terms of absolute values and change from 
baseline. 
Percentages are calculated considering the patients who have performed the examination. 
Also frequencies and percentages for the investigator judgements, calculated considering the 
patients who have performed the examination at each visit, are reported. 
11.5.8. 
Pregnancy test 
A summary table of Pregnancy test results by cohort and visit will be provided in the TLFs. 
Percentages are calculated considering the patients who have performed the examination. 
11.5.9. 
Additional Safety Analyses 
In addition, and based on safety monitoring performed during the study and preclinical data, the 
following search terms were identified to be applied to the safety database: 
• 
Hyperglycaemia/new onset diabetes mellitus (SMQ) narrow scope 
• 
Noninfectious diarrhoea (SMQ) narrow scope 
• 
Haematopoietic erythropenia (SMQ) 
• 
Oropharyngeal conditions (excl neoplasms, infections and allergies) (SMQ) 
• 
Liver related investigations, signs and symptoms (SMQ) 
• 
Rash, including the following terms: dermatitis (PT), dermatitis acneiform (PT), 
dermatitis psoriasiform (PT), drug eruption (PT), eyelid rash (PT), genital rash (PT), 
mucocutaneous rash (PT), perineal rash (PT), rash (PT), rash erythematous (PT), 
rash follicular (PT), rash generalized (PT), rash macular (PT), rash maculo-papular 
(PT), rash maculovesicular (PT), rash morbilliform (PT), rash nodular (PT), rash 
papular (PT), rash papulosquamous (PT), rash pruritic (PT), rash pustular (PT), rash 
vesicular (PT), rash vulvovaginal (PT). 
For each SMQ, one summary table for all the relevant TEAEs by SOC & PT and one 
corresponding listing will be presented. 
12. Efficacy evaluations 
Efficacy analysis will be performed only through descriptive statistics, no formal hypothesis 
testing will be performed. 


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
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12.1. Efficacy analysis 
The following parameters will be summarized by cohort: 
• 
Best Overall Response 
• 
Disease Control Rate 
• 
Overall Response Rate by time point 
• 
Duration of response (DoR) 
• 
Progression Free survival (PFS) 
• 
Overall Survival (OS). 
All these results will be presented on the Efficacy population by study cohort (Cohort 1, Cohort 
2, 
and 
Cohort 
3+Expansion), 
treatment 
group 
(MEN1611+trastuzumab 
or 
MEN1611+trastuzumab+fulvestrant) and overall. 
 
Best Overall Response (BOR) is derived as follows: 
• 
If a subject has at least one overall response of CR, then BOR is CR; 
• 
If a subject doesn’t have any overall response of CR but has at least one overall 
response of PR, then BOR is PR; 
• 
If a subject doesn’t have any overall response of CR or PR but has at least one 
overall response of SD (or Non CR / Non PD) at least six weeks after the first study 
treatment administration, then BOR is SD (or Non CR / Non PD); 
• 
If a subject doesn’t have any overall response of CR, PR. SD (or Non CR / Non PD) 
after at least 6 weeks from the first intake of MEN1611, but has at least one overall 
response of PD, then BOR is PD; 
• 
In all other cases, BOR is NE. 
 
The Disease Control Rate is calculated as the sum of the BOR rates of complete response 
(CR), partial response (PR) and stable disease (SD). 
 
The Overall Survival (OS) is calculated as: 
• 
In case of all-cause death: 
OS = date of death - date of first study treatment administration + 1 
• 
In case of censored information not for drop-out; 
OS = date of end of observation period (i.e. maximum between end of study and last 


 
 
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follow up date) - date of first study treatment administration + 1 
• 
In case of censored information for drop-out: 
OS = last available date in eCRF - date of first study treatment administration + 1 
 
The Progression-Free Survival (PFS) is calculated as: 
• 
In case of death and/or documented progression: 
PFS = (date of death or date of documented disease progression - date of first study 
treatment administration) + 1 
For subjects who experiences both death and progression disease, the date referred 
to the event that comes first is considered. 
• 
In case of censored information: 
PFS = (date of censoring- date of first study treatment administration) + 1 
Subjects (with at least one post baseline assessment) without documented progression or death 
will be censored at the date of last adequate tumor assessment. 
Subjects without any post-baseline tumor assessments will be censored at the date of first study 
treatment administration, however if the subject dies without any post-baseline tumor 
assessments, this will be counted as an event. 
If the subject progresses or dies after 2 or more consecutive missing assessments, the subject 
will be censored at the time of the latest evaluable RECIST 1.1  
assessment prior to the 2 missed visits (Note: a visit with a response of NA is not considered as 
missed visit ). 
 
Detailed censoring rules are as follows: 
Circumstances 
Options for end-date 
(progression or censoring)
Outcome  
1 
Documented Progression 
(i) Date of documented 
progression  
Progressed  
2 
Death without documented progression 
(i) Date of death  
Progressed 
3 
Documented progression or death after 
exactly one missing assessment  
(i) Date of progression or death 
Progressed  
4 
Documented progression or death after 
two or more missing assessments  
(i) Date of last adequate 
assessment 
Censored  
  
5 
No documented progression and no 
death (with at least one post baseline 
assessment) 
(i) Date of last adequate 
assessment  
Censored  
6 
Treatment discontinuation Reason 
‘Disease progression/clinical 
progression/progression’ without 
(i) Ignore clinical progression 
and follow situations above  
As per above 
circumstances 


 
 
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radiological assessment. 
7 
No baseline tumor assessment 
Date of first study treatment 
administration 
Censored 
8 
No post baseline assessment and no 
death 
Date of first study treatment 
administration 
Censored 
9 
Subject lost to follow-up (or withdrew 
consent) before documented 
progression or death 
(i) Date of last adequate 
assessment  
Censored  
 
The Duration of Response (DR) is calculated as: 
• In case of disease progression: 
DR = date of disease progression – date of first occurrence of a BOR of PR, CR or SD 
+ 1 
• In case of censored information: 
DR = date of last tumor assessment – date of first occurrence of a BOR of PR, CR or 
SD + 1 
Note: subjects with only one assessment post baseline with response equal to PD won’t  be 
counted for  the DR calculation 
12.2. Subgroup analyses 
Not applicable. 
 
12.3. Pharmacokinetic analysis 
The PK analysis of this study will be performed by an external vendor and will not be part of this 
SAP; results will be reported in a dedicated report. 
13. Tables, listings and figures 
13.1. Statistical Analysis Report 
The TLF (Tables, Listings and Figures) will follow the list of tables, plots, and listings agreed with 
the Study Physician. The SAR will follow the list of tables, plots, and listings listed in the following 
section. The index is intended to provide the overall idea of the general output and ordering of the 
SAR, it will not necessarily be reproduced in the SAR. 


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
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13.2. Index of TLFs 
13.2.1. 
Tables 
1. BASELINE 
 
2. 
Table 1.1: Enrollment Status 
3. 
Table 1.2.1: Overall Patients Disposition by Dose Cohort 
 
4. 
Table 1.2.2: Overall Patients Disposition by Treatment Arm 
 
5. 
Table 1.3: Reason of study withdrawal by Dose Cohort 
 
6. 
Table 1.4: Reason of treatment discontinuation by Dose Cohort 
7. 
Table 1.5: Demographic Characteristics by Dose Cohort 
 
8. 
Table 1.6: Disease and Baseline Characteristics by Dose Cohort 
 
9. 
Table 1.7.1: Medical History by System Organ Class and Preferred Term by Dose Cohort  
10. 
Table 1.7.2: Current Medical Condition by System Organ Class and Preferred Term by Dose Cohort    
11. 
Table 1.8.1: Anti-Cancer Medication by ATC Code by Dose Cohort 
 
12. 
Table 1.8.2: Prior Medication by ATC Code by Dose Cohort 
 
13. 
Table 1.8.3: Concomitant Medication by ATC Code by Dose Cohort 
 
14. 
Table 1.8.4: Prior and Concomitant Medication by ATC Code by Dose Cohort 
 
15. 
Table 1.9.1: Procedures History by System Organ Class and Preferred Term by Dose Cohort 
 
16. 
Table 1.9.2: Concurrent Procedures by System Organ Class and Preferred Term by Dose Cohort 
 
17. 
Table 1.10: Prior Radiotherapy by Dose Cohort 
 
18. 
Table 1.11: Substance Use by Dose Cohort  
19. 
Table 1.12: Overall summary of Virology at Baseline by Dose Cohort 
 
20. SAFETY TABLES 
 
21. 
Table 2.1.1: Summary of Adverse Events by Dose Cohort      
 
22. 
Table 2.1.2: Summary of Adverse Events by Treatment Arm 
 
23. 
Table 2.1.3: Adverse Events by System Organ Class and Preferred Term by Dose Cohort  
24. 
Table 2.1.4: Serious Adverse Events by System Organ Class and Preferred Term by Dose Cohort  
25. 
Table 2.1.5: Related Adverse Events by System Organ Class and Preferred Term by Dose Cohort  
26. 
Table 2.1.6: Serious and Related Adverse Events by System Organ Class and Preferred Term by Dose 
Cohort  
27. 
Table 2.2.1: Summary of Treatment Emergent Adverse Events by Dose Cohort 
 
28. 
Table 2.2.2: Summary of Treatment Emergent Adverse Events by Treatment Arm 
29. 
Table 2.2.3: Treatment Emergent Adverse Events by System Organ Class and Preferred Term by Dose 
Cohort  
30. 
Table 2.2.4: Treatment Emergent Adverse Events by Grade, System Organ Class and Preferred Term by 
Dose Cohort 
 
31. 
Table 2.2.5: Treatment Emergent Adverse Events by Grade Category, System Organ Class and Preferred 
Term by Dose Cohort 
 
32. 
Table 2.2.6: Treatment Emergent Adverse Events leading to Drug Interruption by System Organ Class and 
Preferred Term by Dose Cohort 
 
33. 
Table 2.2.7: Treatment Emergent Adverse Events leading to Drug Withdrawal by System Organ Class and 
Preferred Term by Dose Cohort 
 
34. 
Table 2.2.8: Treatment Emergent Adverse Events leading to Dose Modification by System Organ Class and 
Preferred Term by Dose Cohort 
 
35. 
Table 2.2.9: Treatment Emergent Adverse Events leading to Death by System Organ Class and Preferred 
Term by Dose Cohort 
 
36. 
Table 2.3.1: Related Treatment Emergent Adverse Events by System Organ Class and Preferred Term by 
Dose Cohort 
 


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
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37. 
Table 2.3.2: Related Treatment Emergent Adverse Events by Grade, System Organ Class and Preferred 
Term by Dose Cohort 
 
38. 
Table 2.3.3: Related Treatment Emergent Adverse Events by Grade Category, System Organ Class and 
Preferred Term by Dose Cohort 
 
39. 
Table 2.3.4: Related Treatment Emergent Adverse Events leading to Drug Interruption by System Organ 
Class and Preferred Term by Dose Cohort 
 
40. 
Table 2.3.5: Related Treatment Emergent Adverse Events leading to Drug Withdrawal by System Organ 
Class and Preferred Term by Dose Cohort 
 
41. 
Table 2.3.6: Related Treatment Emergent Adverse Events leading to Dose Modification by System Organ 
Class and Preferred Term by Dose Cohort 
 
42. 
Table 2.3.7: Related Treatment Emergent Adverse Events leading to Death by System Organ Class and 
Preferred Term by Dose Cohort 
 
43. 
Table 2.4.1: Serious Treatment Emergent Adverse Events by System Organ Class and Preferred Term by 
Dose Cohort 
 
44. 
Table 2.4.2: Serious Treatment Emergent Adverse Events by Grade, System Organ Class and Preferred 
Term by Dose Cohort 
 
45. 
Table 2.4.3: Serious Treatment Emergent Adverse Events by Grade Category, System Organ Class and 
Preferred Term by Dose Cohort 
 
46. 
Table 2.4.4: Serious Treatment Emergent Adverse Events leading to Drug Interruption by System Organ 
Class and Preferred Term by Dose Cohort 
 
47. 
Table 2.4.5: Serious Treatment Emergent Adverse Events leading to Drug Withdrawal by System Organ 
Class and Preferred Term by Dose Cohort 
 
48. 
Table 2.4.6: Serious Treatment Emergent Adverse Events leading to Dose Modification by System Organ 
Class and Preferred Term by Dose Cohort 
 
49. 
Table 2.4.7: Serious Treatment Emergent Adverse Events leading to Death by System Organ Class and 
Preferred Term by Dose Cohort 
 
50. 
Table 2.5.1: Serious and Related Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term by Dose Cohort 
 
51. 
Table 2.5.2: Serious and Related Treatment Emergent Adverse Events by Grade, System Organ Class and 
Preferred Term by Dose Cohort 
 
52. 
Table 2.5.3: Serious and Related Treatment Emergent Adverse Events by Grade Category, System Organ 
Class and Preferred Term by Dose Cohort 
 
53. 
Table 2.5.4: Serious and Related Treatment Emergent Adverse Events leading to Drug Interruption by 
System Organ Class and Preferred Term by Dose Cohort 
 
54. 
Table 2.5.5: Serious and Related Treatment Emergent Adverse Events leading to Drug Withdrawal by 
System Organ Class and Preferred Term by Dose Cohort 
 
55. 
Table 2.5.6: Serious and Related Treatment Emergent Adverse Events leading to Dose Modification by 
System Organ Class and Preferred Term by Dose Cohort 
 
56. 
Table 2.5.7: Serious and Related Treatment Emergent Adverse Events leading to Death by System Organ 
Class and Preferred Term by Dose Cohort 
 
57. 
Table 2.6.1: Hyperglycaemia/New Onset Diabetes Mellitus (SMQ) Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term by Dose Cohort 
 
58. 
Table 2.6.2: Non-Infectious Diarrhoea (SMQ) Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term by Dose Cohort 
59. 
Table 2.6.3: Haematopoietic Erythropenia (SMQ) Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term by Dose Cohort 
 
60. 
Table 2.6.4:  Oropharyngeal Conditions (excl Neoplasms, Infections and Allergies) (SMQ) Treatment 
Emergent Adverse Events by System Organ Class and Preferred Term by Dose Cohort 
 
61. 
Table 2.6.5:  Liver Related Investigations, Signs and Symptoms (SMQ) Treatment Emergent Adverse 
Events by System Organ Class and Preferred Term by Dose Cohort 
 


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
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62. 
Table 2.6.6: Rash (SMQ) Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
by Dose Cohort  
63. 
Table 2.7: Dose Limiting Toxicities by System Organ Class and Preferred Term by Dose Cohort 
 
64. 
Table 2.8: Treatment Exposure and Compliance by Dose Cohort 
 
65. 
Table 2.9.1: Overall summary of Haematology Laboratory Parameters by Visit and Dose Cohort 
 
66. 
Table 2.9.2: Overall summary of Change from Baseline Haematology Laboratory Parameters by Visit and 
Dose Cohort 
 
67. 
Table 2.9.3: Overall summary of Biochemistry Laboratory Parameters by Visit and Dose Cohort 
 
68. 
Table 2.9.4: Overall summary of Change from Baseline Biochemistry Laboratory Parameters by Visit and 
Dose Cohort 
 
69. 
Table 2.9.5: Overall summary of Coagulation Laboratory Parameters by Visit and Dose Cohort 
 
70. 
Table 2.9.6: Overall summary of Change from Baseline Coagulation Laboratory Parameters by Visit and 
Dose Cohort 
 
71. 
Table 2.9.7: Overall summary of Haematology Laboratory Parameters Investigator Assessment by Visit and 
Dose Cohort 
 
72. 
Table 2.9.8: Overall summary of Biochemistry Laboratory Parameters Investigator Assessment by Visit and 
Dose Cohort 
 
73. 
Table 2.9.9: Overall summary of Coagulation Laboratory Parameters Investigator Assessment by Visit and 
Dose Cohort 
 
74. 
Table 2.9.10: Overall summary of Urinalysis Laboratory Parameters Investigator Assessment by Visit and 
Dose Cohort 
 
75. 
Table 2.10.1: Overall summary of 12-lead ECG Parameters by Visit and Dose Cohort 
 
76. 
Table 2.10.2: Overall summary of Change from Baseline 12-lead ECG Parameters by Visit and Dose Cohort 
77. 
Table 2.10.3: Overall summary of      Echocardiography Parameters by Visit and Dose Cohort 
 
78. 
Table 2.10.4: Overall summary of Change from Baseline in Echocardiography Parameters by Visit and Dose 
Cohort  
79. 
Table 2.10.5: Overall summary of 12-lead ECG Investigator Assessment by Visit and Dose Cohort  
80. 
Table 2.10.6: Overall summary of Echocardiography Investigator Assessment by Visit and Dose Cohort 
81. 
Table 2.11: Overall summary of ECOG Performance Status by Visit  and Dose Cohort 
82. 
Table 2.12.1: Overall summary of Vital Signs by Visit and Dose Cohort  
83. 
Table 2.12.2: Overall summary of Change from Baseline Vital Signs Parameters by Visit and Dose Cohort 
84. 
Table 2.12.3: Overall summary of Vital Signs Investigator Assessment by Visit and Dose Cohort 
 
85. 
Table 2.13: Overall summary of Pregnancy Test Visit by Dose Cohort 
86. 
Table 2.14: Overall summary of Physical Examination Investigator Assessment by Visit and Dose Cohort 
87.EFFICACY TABLES 
88. 
Table 3.1.1: Summary of Tumor Response Endpoints by Dose Cohort – Local radiology assessment 
according to RECIST v.1.1  
89. 
Table 3.1.2: Summary of Tumor Response Endpoints by Treatment Arm – Local radiology assessment 
according to RECIST v.1.1  
90. 
Table 3.1.3: Summary of Tumor Response Endpoints by Dose Cohort – Central radiology assessment 
according to RECIST v.1.1  
91. 
Table 3.1.4: Summary of Tumor Response Endpoints by Treatment Arm – Central radiology assessment 
according to RECIST v.1.1  
92. 
Table 3.2.1: Overall Response Rate by Timepoint and Dose Cohort – Local radiology assessment according 
to RECIST v.1.1  
93. 
Table 3.2.2: Overall Response Rate by Timepoint and Treatment Arm – Local radiology assessment 
according to RECIST v.1.1  
94. 
Table 3.2.3: Overall Response Rate by Timepoint and Dose Cohort – Central radiology assessment 
according to RECIST v.1.1  


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
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95. 
Table 3.2.4: Overall Response Rate by Timepoint and Treatment Arm – Central radiology assessment 
according to RECIST v.1.1  
96. 
Table 3.3.1: Summary of Time to Event Endpoints by Dose Cohort 
 
97. 
Table 3.3.2: Summary of Time to Event Endpoints by Treatment Arm 
 
13.2.2. 
 Listings 
98.LISTINGS 
 
99. 
Listing 5.1: Demographic Characteristics 
100. 
Listing 5.2: Reason of study withdrawals 
 
101. 
Listing 5.3: Reason of treatment discontinuation 
 
102. 
Listing 5.4: Pre-Screening Characteristics 
 
103. 
Listing 5.5: Tumor History Characteristics 
 
104. 
Listing 5.6: Tumor History Previous Treatment 
 
105. 
Listing 5.7: Medical History 120 
106. 
Listing 5.8: Prior and Concomitant Medication 
 
107. 
Listing 5.9: Procedures 
 
108. 
Listing 5.10: Adverse Events 
 
109. 
Listing 5.11: Treatment Emergent Adverse Events 
 
110. 
Listing 5.12: Dose Limiting Toxicities by SOC and PT  
111. 
Listing 5.13: Serious Treatment      Emergent Adverse Events  
112. 
Listing 5.14: Related Treatment Emergent Adverse Events 
 
113. 
Listing 5.15:      Serious and Related Treatment Emergent Adverse Events 
 
114. 
Listing 5.16:  Hyperglycaemia/New Onset Diabetes Mellitus (SMQ) Treatment Emergent Adverse Events 
115. 
Listing 5.17:  Non-infectious Diarrhoea (SMQ) Treatment Emergent Adverse Events 
 
116. 
Listing 5.18:  Haematopoietic Erythropenia (SMQ) Treatment Emergent Adverse Events 
 
117. 
Listing 5.19:  Oropharyngeal conditions (excl neoplasms, infections and allergies) (SMQ) Treatment 
Emergent Adverse Events  
118. 
Listing 5.20:  Liver related investigations, signs and symptoms (SMQ) Treatment Emergent Adverse Events 
119. 
Listing 5.21:  Rash Treatment Emergent Adverse Events 
120. 
Listing 5.22: Haematology  
121. 
Listing 5.23: Biochemistry  
122. 
Listing 5.24: Coagulation  
123. 
Listing 5.25: Urinalysis 
 
124. 
Listing 5.26: Virology 
 
125. 
Listing 5.27: 12-lead ECG  
126. 
Listing 5.28: Echocardiography 
 
127. 
Listing 5.29: ECOG Performance Status 
 
128. 
Listing 5.30: Physical Examination 
129. 
Listing 5.31: Vital Signs 
 
130. 
Listing 5.32: Pregnancy test 
 
131. 
Listing 5.33: Treatment Intake – MEN1611 
 
132. 
Listing 5.34: Treatment Intake – Trastuzumab 
 
133. 
Listing 5.35: Treatment Intake – Fulvestrant  
134. 
Listing 5.36: Tumor Lesion – Local assessment 
 
135. 
Listing 5.37: Tumor Lesion – Central assessment 
 
136. 
Listing 5.38: Tumor Response by Timepoint – Local assessment according to RECIST v.1.1 
 
137. 
Listing 5.39: Tumor Response by Timepoint – Central assessment according to RECIST v.1.1 
 


 
 
Study code: MEN1611-01                                    Statistical Analysis Plan (SAP) 
EudraCT no.: 2017-004631-36                             Version n.1.0, 11AUG2023 
 
 
MR-GCS-DMST-210.A_Template – Statistical Analysis Plan                                                 Version 1, Eff. date 31-March-2022  
 
 
 
 
 
 
    
 
 
 
 
 
     Page 49 of 49 
 
 
13.2.3. 
Figures 
138. Figures 
 
139. 
Figure 6.1: Kaplan-Meier Curve of Duration of Response - Local Assessment 
 
140. 
Figure 6.2: Kaplan-Meier Curve of Duration of Response - Central Assessment 
 
141. 
Figure 6.3: Kaplan-Meier Curve of Progression-free Survival - Local Assessment  
142. 
Figure 6.4: Kaplan-Meier Curve of Progression-free Survival - Central Assessment 
 
143. 
Figure 6.5: Kaplan-Meier Curve of Progression-free Survival