Open-label, Multicentre, Phase Ib/II Study of MEN1611, a PI3K Inhibitor, and Cetuximab in Patients With PIK3CA Mutated Metastatic Colorectal Cancer Failing Irinotecan, Oxaliplatin, 5-FU and Anti-EGFR Containing Regimens
Phase: PHASE1
Conditions: Metastatic Colorectal Cancer
Sponsor: Menarini Group

CLINICAL TRIAL PROTOCOL 
FINAL VERSION 5.0, 15 MAY 2023 
OPEN-LABEL, MULTICENTRE, PHASE IB/II STUDY OF 
MEN1611, A PI3K INHIBITOR, AND CETUXIMAB IN PATIENTS 
WITH PIK3CA MUTATED METASTATIC COLORECTAL CANCER 
FAILING IRINOTECAN, OXALIPLATIN, 5-FU AND ANTI-EGFR 
CONTAINING REGIMENS 
Study Code: 
MEN1611-02 
Study Nick Name/Acronym: 
C-PRECISE-01 
EudraCT Number: 
2019-003727-38 
Investigational Medicinal Product: MEN1611 oral capsules 
Development Phase of the Study: 
Phase Ib/II 
SPONSOR 
CO-ORDINATING INVESTIGATOR 
CONTRACT RESEARCH 
ORGANISATION 
Menarini Ricerche S.p.A. 
Clinical Sciences 
Via Sette Santi, 1 
50131 Florence, Italy 
Phone: +39 055 5680 9990 
Fax:+39 055 5680 597 
 
Vall d'Hebron University Hospital 
Vall d' Hebron Institute of Oncology (VHIO) 
P. Vall d'Hebron 119-129
08035 Barcelona. Spain
Phone: 
IQVIATM 
3 Forbury Place, 
23 Forbury Road  
Reading 
RG1 3JH, 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 #: NCT04495621

Clinical Trial Protocol 
EudraCT No.: 2019-003727-38 
1 
SIGNATURES 
C·PRE@ ISE·01 
COi.ON-A Pl3KINHlll!Oft\\lTHWIGEIED C-TIONS IN SDIJO llf.tOffi TllfAThlEl/f 
Study Code MENl 611-02 
Final Version 5.0 
15 May 2023 
The Signatories have read the clinical study protocol (Version 5.0, dated 15 May 2023) titled "Open-
labe~ Multicentre, Phase lb/II Study of MENJ 611, a PI3K Inhibitor, and Cetuximab in Patients 
with PIK3CA Mutated Metastatic Colorectal Cancer Failing Irinotecan, Oxaliplatin, 5-FU and 
Anti-EGFR Containing Regimens" 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. 
Menarini Ricerche S.p.A. 
Vall d'Hebron University Hospital 
Vall d'Hebron Institute of Oncology 
(VHIO) 
Signature 
Signature 
Confidential 
Menarini Ricerche S.p.A. 
Date 
28-JUN-2023 
Date 
2 of 155 

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Study Code MEN1611-02 
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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 15 May 2023) titled “Open-label, Multicentre, Phase Ib/II Study of MEN1611, 
a PI3K Inhibitor, and Cetuximab in Patients with PIK3CA Mutated Metastatic Colorectal Cancer 
Failing Irinotecan, Oxaliplatin, 5-FU and Anti-EGFR Containing Regimens” 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  
MEN1611-02 
Title 
Open-label, Multicentre, Phase Ib/II Study of MEN1611, a PI3K 
Inhibitor, and Cetuximab in Patients with PIK3CA Mutated 
Metastatic Colorectal Cancer Failing Irinotecan, Oxaliplatin, 5-FU 
and Anti-EGFR Containing Regimens 
Acronym 
C-PRECISE-01 
Phase 
Ib/II 
Indication 
Phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene 
(PIK3CA) mutated, N-K-RAS and BRAF wild type, metastatic 
colorectal cancer, in patients failing irinotecan, oxaliplatin, 5-FU 
and anti- epidermal growth factor receptor (EGFR) containing 
regimens. 
Number of Sites and 
Countries 
Approx. 29 sites in Europe and US. 
Investigational Medicinal 
Product, Treatment 
Regimen (including route of 
administration) 
MEN1611, oral capsule: 16 mg capsules to be administered twice 
daily (BID) for a continuous 28-day cycle. Patients will receive 
MEN1611 either 48 mg or 32 mg BID (as 3 or 2 capsules, 
respectively), for a total daily dose of 96 mg or 64 mg, respectively. 
MEN1611 should be taken with a glass of water in fasting 
condition, i.e. at least 2 hours after the patient’s meal and at least 
1 hour before the next mealPatients should take capsules at 
approximately the same time each day. 
Cetuximab, solution for infusion: A loading intravenous (IV) dose 
of 400 mg/m2 of cetuximab is administered as a 120 minutes 
infusion on Day 1 of Cycle 1, followed by weekly IV infusion 
(60 minutes) of 250 mg/m2 maintenance doses starting from Day 8 
of Cycle 1. Premedication with a corticosteroid and a histamine-1 
(H1) 
receptor 
antagonist 
(e.g. 
d-chlorpheniramine 
or 
diphenhydramine) is required prior to cetuximab administration. 
Infusion reactions due to cetuximab are to be managed according to 
Section 8.4.5. 

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MEN1611 will be given in combination with weekly IV infusion of 
cetuximab until objective disease progression is documented or 
another criterion for discontinuation is met. If cetuximab needs to 
be discontinued due to toxicity, patients may stay on study to 
receive MEN1611 as monotherapy. 
Design 
 
This is an open-label, dose-confirmation and cohort expansion, 
multicentre, Phase Ib/II study. 
Step 1 (Confirmation of Dose for Cohort Expansion): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Step 2 (Cohort Expansion Phase): 
 
 
  
 
 
 
DLT 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, cetuximab or both given in 
combination. Toxicities will be graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events 

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version 5.0 (NCI CTCAE v5.0), except for segmental wall-motion 
abnormalities (not described in NCI CTCAE v5.0). 

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Objectives 
Primary: 
Step 1 
 To determine the RP2D of MEN1611 when administered 
orally in combination with cetuximab to patients with 
PIK3CA mutated colorectal cancer failing irinotecan, 
oxaliplatin, 5-FU, and anti-EGFR containing regimens. 
Step 2: 
 To assess the anti-tumour activity of MEN1611 in 
combination with cetuximab in patients with PIK3CA 
mutated metastatic colorectal cancer failing irinotecan, 
oxaliplatin, 5-FU, and anti-EGFR containing regimens. 
Secondary: 
 To assess the safety and tolerability of MEN1611 in 
combination with cetuximab. 
 To assess the pharmacokinetic (PK) profile of MEN1611 
when given in combination with cetuximab. 
Exploratory: 

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Study Duration 
The overall study duration will depend on the completion of the 
dose levels/cohorts, the number of patients to be treated per each 
dose-cohort and the completion of Step 2 up to a total of 40 
evaluable patients for efficacy. 
All patients pre-screened for the PIK3CA mutation will undergo a 
maximum 4 weeks Screening Period.  
Each treatment cycle will last 28 days.  
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 after the last dose 
of MEN1611. 
 
Survival Follow-up: 
After the End of Study Visit, all patients evaluable for efficacy will 
be followed for survival status according to local practice (a visit or 
a telephone call) every 12 weeks up to the End of Study. 
 
End of Study: 
The study ends with the End of Study Visit of the last patient 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 
the End of Study must be recorded and notified to the Sponsor. 

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Inclusion Criteria 
Patients meeting all the following criteria will be eligible for entry 
into the pre-screening: 
1. Able to give written informed consent. 
2. Metastatic colorectal cancer (mCRC). 
3. Progression or recurrence following prior anti-EGFR 
containing regimen and at least in second line of treatment 
for mCRC. 
4. Known N-K-RAS (exons 2, 3 and 4) wild-type status. 
5. Known BRAF wild-type or unknown BRAF status.  
6. Male and female aged ≥ 18 years. 
Patients meeting all the following criteria at Screening Visit will be 
eligible for entry into the study: 
1. Able to give written informed consent before any study 
related procedure. 
2. Histological documentation of adenocarcinoma of the colon 
or rectum with radiological evidence of progressive disease 
after last treatment received. 
3. Progression or recurrence following irinotecan, oxaliplatin, 
fluoropyrimidine containing regimen and anti-EGFR 
containing regimens for metastatic disease. Patients who 
have a history of intolerance of irinotecan-based therapy or 
who are ineligible to receive irinotecan are also eligible as 
long as they have received a prior oxaliplatin-based therapy. 
Patients who have a history of intolerance of oxaliplatin-
based therapy or who are ineligible to receive oxaliplatin are 
also eligible as long as they have received a prior irinotecan-
based therapy. 
4. Best response according to Response Evaluation Criteria in 
Solid Tumours (RECIST) criteria to the last anti-EGFR 
containing regimen of partial response (PR) or stable 
disease (SD) for at least 4 months. 

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5. Measurable disease according to RECIST criteria, version 
1.1. 
6. Having a tumour N-K-RAS (exons 2, 3 and 4) and BRAF 
wild-type harbouring a PIK3CA mutation, as per centrally-
analysed ctDNA during the [pre]-screening period using a 
validated test. 
7. Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 0 or 1. 
8. Life expectancy ≥ 12 weeks. 
9. Adequate cardiac function as defined by left ventricular 
ejection fraction of ≥ 50% measured by a multigated 
acquisition (MUGA) scan or echocardiography (ECHO). 
10. Adequate bone marrow function as defined by ANC of 
≥ 1.5x 109/L, platelet count of ≥ 100.0x 109/L and 
haemoglobin of ≥ 9 g/dL. 
11. Adequate liver function, as determined by total bilirubin 
within ULN (≤ 1.5x ULN if documented liver involvement; 
≤ 3x ULN with direct bilirubin ≤ 1.5x ULN in case of 
patients with coexisting known Gilbert’s disease) and/or 
AST and ALT ≤ 2.5x ULN (≤ 5x ULN if liver metastases). 
12. Adequate renal function assessed by creatinine clearance 
≥50 mL/min (calculated by Cockcroft-Gault formula).  
13. Adequate electrolytes (serum potassium and magnesium 
levels within institutional normal limits). Replacement 
treatment to achieve adequate electrolytes levels is allowed. 
14. Not pregnant, not breastfeeding, and at least 1 of the 
following conditions applies: 
a) Not a woman of childbearing potential (WOCBP) (see 
Appendix I, Section 13.1). 
OR 
b) A WOCBP who agrees to use highly effective 
contraception 4 weeks before the first dose of the study 
treatment, during the treatment period and for 6 months 
following the last dose of the study treatment. Patients 

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should not breastfeed during and at least for 6 months 
after the last dose of the study treatment. 
15. Male patient who is surgically sterile or male patient who is 
willing to agree and have his female partners (if WOCBP) 
agreeing with the true abstinence (refrain from heterosexual 
intercourse) or who agrees to use and to have his female 
partners (if WOCBP) using barrier contraceptive measures 
during the entire study treatment period and for 6 months 
after the last administration of study treatment, and agrees 
to refrain from donating sperm during the entire study 
treatment period and for 6 months after the last 
administration of study treatment. 
Note: Inclusion criteria 7 and 10 to 13 (if applicable) will be 
re-evaluated prior to the start of any study treatment (Day 1 of 
Cycle 1). 
Exclusion Criteria 
Patients will not be eligible for entry into the pre-screening if 
they meet ANY of the following exclusion criteria: 
1. Patients with a known PIK3CA wild-type status.  
2. Note: this exclusion criterion does not apply if PIK3CA 
wild-type status was assessed before the last anti-EGFR 
containing regimen.  
3. Previous treatment with phosphatidylinositol 3-kinase 
(PI3K) inhibitor. 
4. Hypersensitivity and/or contraindication to MEN1611, 
cetuximab or to any component of the formulations. 
5. Inability or unwillingness to abide by the study protocol; 
legal incapacity or limited legal capacity. 
None of the following exclusion criteria shall be met at Screening 
Visit and will be re-checked at Day 1 of Cycle 1: 

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1. Previous treatment with a PI3K inhibitor. 
2. Hypersensitivity and/or contraindication to MEN1611, 
cetuximab or to any component of the formulations. 
3. Inability to swallow oral medications. 
4. Brain metastases, with the exception of patients with 
previously treated brain metastases (including radiation 
and/or surgery) > 4 weeks before the Screening Visit and 
only if clinically stable (as determined by the Investigator), 
and not receiving corticosteroids. 
5. NCI CTCAE v5.0 Grade ≥ 2 diarrhoea, which is not 
resolved in the week prior to the start of the study treatment 
(Day 1 of Cycle 1). 
6. History of significant, uncontrolled or active cardiovascular 
disease, specifically including, but not restricted to: 
a) Myocardial infarction within 6 months prior to the first 
dose of any study treatment (Day 1 of Cycle 1). 
b) Acute coronary syndromes (including unstable angina, 
coronary artery bypass grafting [CABG], coronary 
angioplasty or stenting) within 6 months prior to first 
dose of any study treatment (Day 1 of Cycle 1). 
c) Congestive heart failure (CHF) New York Heart 
Association Class III-IV. 
d) Clinically significant atrial arrhythmia (including 
clinically significant bradyarrhythmia), as determined 
by the Investigator. 
e) Long QT syndrome or other risk factors for “Torsades 
de Pointes” or increased QT interval (QTc) according to 
Fridericia formula (QTcF > 450 msec for males and 
QTcF > 460 msec for females). 
f) Ventricular arrhythmia.  
7. Symptomatic thromboembolic events or cerebrovascular 
accident including transient ischaemic attack within 
6 months prior to the start of any study treatment (Day 1 of 
Cycle 1). 

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8. Uncontrolled hypertension (defined as persistent blood 
pressure [BP] of ≥ 150/90 mmHg despite treatment, 
measured on at least 2 separate occasions). 
9. Known active or uncontrolled pulmonary dysfunction. 
10. Any serious and/or unstable pre-existing psychiatric or 
neurologic illness or other conditions that could interfere 
with patient’s safety. 
11. Uncontrolled diabetes mellitus (glycated haemoglobin 
[HbA1c] > 7%) and fasting plasma glucose (FPG) 
> 126 mg/dL. 
12. Known history of human immunodeficiency virus (HIV) 
infection or active infection with hepatitis C virus (HCV) or 
hepatitis B virus (HBV).  
13. Patients diagnosed with another primary malignancy, 
except for: Adequately treated non-melanoma skin cancer 
or cervical cancer in situ; or patients with another primary 
malignancy who are definitively relapse-free for at least 
3 years since the diagnosis of the other primary malignancy. 
14. Concurrent chronic immunosuppressive treatment either 
with steroids or other immunosuppressive agents. 
15. Any chemotherapy, radiotherapy, immunotherapy, major 
surgery, biologic therapy or any other investigational agent 
within 28 days of the first administration of the study 
treatment or within five times the half-life of the 
investigational agent, whichever is longer. 
Note: Patients may receive palliative radiotherapy for 
painful bone metastases, as long as ≤ 25% of the bone 
marrow was irradiated and does not affect target and non-
target lesions being assessed. (Please see section 8.4.8.) 
16. 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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17.
 
s 
 
 
 
 
18. Pregnant or breastfeeding women. 
19. Inability or unwillingness to abide by the study protocol; 
legal incapacity or limited legal capacity. 
20. Warfarin sodium therapy or any other coumadin-derivative 
anticoagulant. 
Study Procedures and 
Efficacy, Pharmacokinetic, 
Pharmacodynamic and 
Safety Assessments 
(see also flow chart) 
Pre-screening Period: 
At the Pre-screening Visit, all pre-screening eligible patients will 
perform mutational analysis for PIK3CA, BRAF and N-K-RAS in 
plasma (ctDNA centrally analysed) following provision of the 
written pre-screening informed consent. Inclusion into the study 
will be done based on the results of the ctDNA.  
Screening Period (Day -28 to Day -1): 
During the 28 days prior to the first dose of MEN1611 and 
following provision of written informed consent, each patient will 
be screened for eligibility. Patients entering the screening period 
with pre-screening ctDNA test older than 3 months need to be 
centrally re-tested for PIK3CA, N-K-RAS and BRAF in plasma. 
The following procedures will be performed at Screening: 
 Check of inclusion/exclusion criteria. 
 Recording of demographic data. 
 Standard medical, surgical and medication history. 
 Assessment of ECOG PS. 
 Smoking history and current smoking status. 
 Physical examination including vital signs (i.e. BP, heart 
rate, respiratory rate, body temperature) and weight. 
 Recording of AEs and concomitant medications. 
 12-lead electrocardiogram (ECG) record. 

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 Tumour assessment using RECIST v1.1 for patients with 
measurable disease not older than 2 weeks as assessed by: 
- Computed tomography (CT) scan with IV contrast 
medium of chest, abdomen and pelvis as preferred 
technique. If contraindications to contrast medium are 
present, a CT scan without contrast medium of chest and 
a magnetic resonance imaging (MRI) of abdomen and 
pelvis could be used.  
- MRI or CT scan of the brain in patients with a history of 
asymptomatic brain metastases. 
- Whole body bone scan, if clinically indicated.  
 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, 
hepatitis 
B 
surface 
antigen 
(HBsAg), 
HBV-
deoxyribonucleic acid (HBV-DNA), HCV-ribonucleic acid 
(HCV-RNA). 
Note: In case the laboratory tests for anti-HIV antibodies, anti-
HBcAg antibodies, anti-HBsAg antibodies, HBsAg, HBV-DNA 
and HCV-RNA have been performed within 3 months prior to 
Screening Period in the context of the standard patient’s 
management; these tests will not be repeated. 
 Blood samples for ctDNA ONLY if pre-screening ctDNA 
test is older than 3 months. 
 Serum pregnancy test (if applicable). 
 Sample for urinalysis. 
A screen failure is defined as follows: 
 A patient who does not meet the eligibility criteria required 
for study participation at Screening. 
 A patient who does not meet eligibility criteria at study 
Visit 1 (Day 1) of Cycle 1, when applicable. 

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 Time window between Screening and Visit 1 (i.e. Day 1 of 
Cycle 1, when applicable) is longer than 4 weeks. 
Note-1: Study procedures under Screening Visit may occur also on 
more than one day. 
Note-2: Results of safety laboratory tests (chemistry, haematology, 
coagulation, urinalysis and pregnancy test, when appropriate), and 
ECG, which have been performed in the context of the standard 
patient’s management, can be recorded in the electronic case report 
form (eCRF) under Screening Visit procedures, provided that they 
have been done the day before the start of Screening Period. 
Note-3: If the complete assessment of the eligibility criteria is 
available within 3 days from the end of the Screening Period, the 
patient’s participation in the trial can be discussed with the Sponsor 
Medical Monitor. 
Screen failures can be re-screened upon Sponsor Medical Monitor’s 
approval. 
Cycle 1: 
Visit 1 – start of MEN1611 treatment (Day 1): 
(All assessments can be performed within 48 hours prior to 
administration of the study treatment at site, unless otherwise 
indicated.) 
 Re-evaluation 
of 
inclusion/exclusion 
criteria 
and 
confirmation of patient’s eligibility prior to the start of the 
study treatment. 
 tumour assessment using RECIST v1.1 for patients with 
measurable disease performed within the last 4 weeks as 
assessed by: 
- CT scan with IV contrast medium of chest, abdomen and 
pelvis as preferred technique. If contraindications to 
contrast medium are present, a CT scan without contrast 
medium of chest and a MRI of abdomen and pelvis could 
be used.  

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- MRI or CT scan of the brain in patients with a history of 
asymptomatic brain metastases. 
- Whole body bone scan, if clinically indicated.   
Note: Tumour assessment will not be repeated when already 
performed within 4 weeks prior to Visit 1, Day 1. 
 Physical examination including vital signs (i.e. BP, heart 
rate, respiratory rate, body temperature), height and weight. 
 Blood sample for CTC enumeration before the treatment. 
 Assessment of ECOG PS. 
 Blood samples for haematology, coagulation and chemistry 
including HbA1c. 
 Serum pregnancy test (if applicable). 
 Sample for urinalysis. 
 12-lead ECG record (pre-dose). 
 12-lead ECG record (2 hours post first daily MEN1611 dose 
administration). 
 
  
 
 
 
  
 
 
 Dispensing of the patient diary for study treatment 
compliance. 
 Instructions for MEN1611 administration for the following 
days at home. 
 Recording of AEs and concomitant medications. 
 Cohort assignment. 
 Study treatment administration, according to the following 
order: 
- Premedication with a corticosteroid and a H1 receptor 
antagonist 30-60 minutes prior to the cetuximab 
application. 

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- Cetuximab 400mg/m2 as a 120 minutes IV infusion. 
- Dispensing of MEN1611 and administration in fasting 
condition of the first assigned dose (48 mg or 32 mg as 3 
or 2 capsules BID, respectively). 
Note: Patients will be monitored at the site for occurrence of AE 
during cetuximab infusion and for at least 1 hour after the end of 
infusion. 
 
Visit 2 (Day 8), Visit 3 (Day 15) and Visit 4 (Day 22): 
(All assessments can be performed within 48 hours prior to 
administration of the study treatment at site, unless otherwise 
indicated.) 
 Physical examination including vital signs (i.e. BP, heart 
rate, respiratory rate, body temperature) and weight. 
 Assessment of ECOG PS. 
 12-lead ECG record (pre-dose, ONLY at DAY 15). 
 12-lead ECG record (2 hours post first daily MEN1611 dose 
administration, ONLY at DAY 15). 
 Blood samples for haematology, coagulation and chemistry. 
 Recording of AEs and concomitant medications. 

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 Study treatment administration, according to the following 
order: 
- Premedication with a corticosteroid and a H1 receptor 
antagonist 30-60 minutes prior to the cetuximab 
application. 
- Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- Dispensing of MEN1611 and administration in fasting 
condition of the first assigned dose (48 mg or 32 mg as 
3 or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE 
during cetuximab infusion and after the end of infusion for at least 
1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular 
disorders Grade ≥ 2 are assessed (the AE has to be followed until 
resolution to Grade 1). A dermatological visit shall be performed in 
case skin toxicity Grade ≥ 3 is assessed (the AE has to be followed 
until resolution to Grade 1). The frequency of ophthalmic and 
dermatological visits can be increased upon Investigator’s 
judgement. 
 
Cycle 2: 
Visit 1 (Day 1) (+ 5-Day window): 
(All assessments can be performed within 48 hours prior to 
administration of the study treatment at site, unless otherwise 
indicated.) 
 Physical examination including vital signs (i.e. BP, heart 
rate, respiratory rate, body temperature) and weight. 
 Blood sample for CTC enumeration before the treatment. 
 
 
 Assessment of ECOG PS. 
 12-lead ECG. 
 Blood samples for haematology, coagulation and chemistry 
including HbA1c. 
 Serum pregnancy test (if applicable). 

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Study Code MEN1611-02 
Final Version 5.0 
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 Sample for urinalysis. 
 Dispensing of the patient diary for study treatment 
compliance. 
 Recording of AEs and concomitant medications. 
 Study treatments administration, according to the following 
order: 
- Premedication with a corticosteroid and a H1 receptor 
antagonist 30-60 minutes prior to the cetuximab 
application. 
- Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- Dispensing of MEN1611 and administration in fasting 
condition of the first assigned dose (48 mg or 32 mg as 3 
or 2 capsules BID, respectively). 
Note: Patients will be monitored at the site for occurrence of AE 
during cetuximab infusion and after the end of infusion for at least 
1 hour. 
 
Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 22): 
(All assessments can be performed within 48 hours prior to 
administration of the study treatment at site, unless otherwise 
indicated.) 
 Physical examination including vital signs (i.e. BP, heart 
rate, respiratory rate, body temperature) and weight. 
 Assessment of 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 
order: 
- Premedication with a corticosteroid and a H1 receptor 
antagonist 30-60 minutes prior to the cetuximab 
application. 

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EudraCT No.: 2019-003727-38 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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- Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- Dispensing of MEN1611 and administration in fasting 
condition of the first assigned dose (48 mg or 32 mg as 3 
or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE 
during cetuximab infusion and after the end of infusion for at least 
1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular 
disorders Grade ≥ 2 are assessed (the AE has to be followed until 
resolution to Grade 1). A dermatological visit shall be performed 
in case skin toxicity Grade ≥ 3 is assessed (the AE has to be 
followed until resolution to Grade 1). The frequency of ophthalmic 
and dermatological visits can be increased upon Investigator’s 
judgement. 
 
Cycle 3 up to Cycle 6:  
Visit 1 (Day 1) (+ 5-Day window)  
(All assessments can be performed within 48 hours prior to 
administration of the study treatment at site, unless otherwise 
indicated.) 
 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: ctDNA levels ONLY at Cycle 3 and CTC 
enumeration ONLY at Cycle 3 and Cycle 5.  
 Tumour assessment using RECIST v1.1 will be performed 
at Cycle 3 and Cycle 5 (within a window of 7 days before 
the visit date).  
 Sample for urinalysis. 
 Assessment of ECOG PS. 

Clinical Trial Protocol 
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Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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 12-lead ECG (same technique used at baseline) will be 
performed ONLY at Cycle 3 and Cycle 5. 
 Dispensing of the patient diary for study treatment 
compliance. 
 Recording of AEs and concomitant medications. 
 Study treatment administration, according to the following 
order: 
- 
Premedication with a corticosteroid and a H1 receptor 
antagonist 30-60 minutes prior to the cetuximab 
application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting 
condition of the first assigned dose (48 mg or 32 mg as 
3 or 2 capsules BID, respectively). 
Note: Patients will be monitored at the site for occurrence of AE 
during cetuximab infusion and after the end of infusion for at least 
1 hour. 
 
Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 22): 
(All assessments can be performed within 48 hours prior to 
administration of the study treatment at site, unless otherwise 
indicated.) 
 Physical examination including vital signs (i.e. BP, heart 
rate, respiratory rate, body temperature) and weight. 
 Assessment of 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 
order: 
- 
Premedication with a corticosteroid and a H1 receptor 
antagonist 30-60 minutes prior to the cetuximab 
application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 

Clinical Trial Protocol 
EudraCT No.: 2019-003727-38 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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- 
Dispensing of MEN1611 and administration in fasting 
condition of the first assigned dose (48 mg or 32 mg as 
3 or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE 
during cetuximab infusion and after the end of infusion for at least 
1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular 
disorders Grade ≥ 2 are assessed (the AE has to be followed until 
resolution to Grade 1). A dermatological visit shall be performed 
in case skin toxicity Grade ≥ 3 is assessed (the AE has to be 
followed until resolution to Grade 1). The frequency of ophthalmic 
and dermatological visits can be increased upon Investigator’s 
judgement. 
 
Cycle 7 Onwards:  
Visit 1 (Day 1) (+ 5-Day window), Visit 2 (Day 8), Visit 3 (Day 
15) and Visit 4 (Day 22) 
(All assessments can be performed within 48 hours prior to 
administration of the study treatment at site, unless otherwise 
indicated.) 
 Physical examination including vital signs (i.e. BP, heart 
rate, respiratory rate, body temperature) and weight. 
 Assessment of ECOG PS. 
 12-lead ECG (same technique used at Baseline) at Day 1 of 
Cycle 7 and then EVERY 2 cycles. 
 Blood samples for haematology, coagulation and chemistry 
including HbA1c ONLY at Day 1. 
 Serum pregnancy test (if applicable) ONLY at Day 1. 
 Sample for urinalysis ONLY at Day 1. 
 Tumour assessment using RECIST v1.1 at Day 1 of Cycle 7 
and then EVERY 2 cycles (within a window of 7 days 
before the visit date).  
 Blood sample for CTC enumeration before the treatment 
ONLY at Day 1 of Cycle 7 and then EVERY 2 cycles. 

Clinical Trial Protocol 
EudraCT No.: 2019-003727-38 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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 Dispensing of the patient diary for study treatment 
compliance at Day 1. 
 Recording of AEs and concomitant medications. 
 Study treatment administration, according to the following 
order: 
- 
Premedication with a corticosteroid and a H1 receptor 
antagonist 30-60 minutes prior to the cetuximab 
application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting 
condition of the first assigned dose (48 mg or 32 mg as 
3 or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE 
during cetuximab infusion and after the end of infusion for at least 
1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular 
disorders Grade ≥ 2 are assessed (the AE has to be followed until 
resolution to Grade 1). A dermatological visit shall be performed in 
case skin toxicity Grade ≥ 3 is assessed (the AE has to be followed 
until resolution to Grade 1). The frequency of ophthalmic and 
dermatological visits can be increased upon Investigator’s 
judgement. 
Note-3: 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). 
 Tumour assessment using RECIST v1.1 will be performed 
if the last assessment is older than 8 weeks.  
 Assessment of ECOG PS. 
 Smoking history and current smoking status. 

Clinical Trial Protocol 
EudraCT No.: 2019-003727-38 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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 Blood samples for haematology, coagulation and chemistry. 
 Sample for urinalysis. 
 Recording of AEs and concomitant medications. 
 Serum pregnancy test (if applicable). 
 ctDNA levels and CTC enumeration assessments. 
Note-1: All patients 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 patient’s withdrawal can replace the End of Study 
Visit provided that all assessment/procedures scheduled for this 
visit are completed. 
Note-2: Images collected at each tumour assessment time point 
have to be uploaded into a dedicated iMedidata Application 
according to the manual for retrospective central analysis. 
Survival Follow-up: 
After the End of Study Visit, all patients evaluable for efficacy will 
be followed for survival status according to local practice (a visit or 
a telephone call) every 12 weeks 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, magnesium, carbohydrate antigen 
19-9 (CA19-9), carcinoembryonic antigen (CEA), total bilirubin, 
direct bilirubin, gamma-glutamyl transpeptidase (GGT), glucose, 
HbA1c, lactate dehydrogenase (LDH), total protein, prothrombin 
time and/or prothrombin activity, international normalised ratio 
(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-

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Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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HBcAg antibodies, anti-HBsAg antibodies, HBsAg, 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 (Identification of Dose for Cohort Expansion): 
 Identification of the dose for the Cohort Expansion, defined 
as the highest dose level (maximum dose tested 48 mg BID, 
minimal dose tested 32 mg BID) at which no more than 1 of 
6 patients experiences a DLT during the DLT assessment 
window (see DLT definition).  
Step 2 (Cohort Expansion Phase): 
 Best overall response rate (ORR) defined according to 
RECIST v1.1 assessment locally performed using 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 patient. 
Secondary: 
 Safety and tolerability:  
- 
Incidence, severity as per CTCAE version 5.0 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 and 12-lead ECG. 
 PK profile: MEN1611 plasma concentration-time data will 
be analysed using a population PK approach. A nonlinear 

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Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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mixed effects model will be used to determine population 
PK parameters and their associated variabilities (e.g. 
apparent systemic clearance [CL/F], [V/F], [Ka]). 
Individual PK parameters (e.g. area under the concentration 
time 
curve 
[AUC], 
maximum 
observed 
plasma 
concentration [Cmax]) will be estimated using a post hoc 
analysis. 
 Disease Control Rate (DCR) defined as percentage of 
patients whose disease shrinks or remains stable over a 
certain time period. DCR is the sum of the complete, partial 
and stable disease rates according to local assessment.  
 Duration of response defined as time from confirmation of 
a PR, complete response (CR) or SD as locally assessed, 
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 as per local 
assessment, relapse or death from any cause. Responding 
patients and patients 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. 
For the baseline assessment, CT scan or MRI should be performed 
no more than 4 weeks before the start of study treatment. Follow-up 
assessment will be performed every 2 cycles during study treatment 
starting from Day 1 Cycle 3 (within a window of 7 days before the 
visit date) 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. 

Clinical Trial Protocol 
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Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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Exploratory: 
Sample size 

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Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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Analysis Populations 
DLT population: 
All patients receiving at least 80% of MEN1611 and 75% of 
cetuximab during Cycle 1 with a Safety Follow-up of 28 days after 
the first administration of the study treatment. Any patient who 
experiences a DLT will also be considered evaluable, regardless of 
the dose of MEN1611 received.  
Patients enrolled in the Dose-confirmation Phase (Step 1), who are 
not DLT evaluable, will be replaced. 
Safety population: 
All patients receiving at least 1 dose of MEN1611. 
Efficacy population: 
All eligible patients who receive at least 2 complete treatment 
cycles and have at least 1 disease assessment are to be considered 
evaluable for efficacy. 
PK population: 
All patients receiving the study treatment and for whom a PK 
sample is obtained and analysed. 
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 
and event rate every 28 days. 
The behaviour over time of study variables will be summarised by 
treatment cohort and overall as follows: 

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Study Code MEN1611-02 
Final Version 5.0 
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 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 patient’s variables will be evaluated calculating 
the appropriate correlation coefficient with the respective statistical 
significance level. 
 
PK Analysis: 
PK analysis will be performed on the PK population. All PK 
variables (i.e. MEN1611 plasma concentrations) will be 
summarised by cohort using the following descriptive statistics: 
 Number of non-missing observations (N). 
 Arithmetic mean and its 90% confidence interval (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 PK endpoints will be described in the PK Data Analysis 
Plan (DAP). 
 
 

Clinical Trial Protocol  
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Study Code MEN1611-02 
Final Version 5.0, 15 May 2023 
 
 
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2.1 Schematic Design: Dose-Confirmation (Step 1) and Cohort-Expansion (Step 2)  
 
BID = twice daily, RP2D = recommended Phase 2 dose 
Note: RP2D to be tested in Step 2 is the 48 mg BID or 32 mg BID if no more than 1 DLT occurs in a total of 6 patients treated in Cohort 1 or in 
Cohort 2, respectively in Step 1 (see Section 8.1). 

Clinical Trial Protocol  
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0, 15 May 2023 
 
 
Confidential 
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Clinical Trial Protocol  
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0, 15 May 2023 
 
 
Confidential 
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Clinical Trial Protocol  
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0, 15 May 2023 
 
 
Confidential 
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Clinical Trial Protocol  
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0, 15 May 2023 
 
 
Confidential 
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Clinical Trial Protocol  
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0, 15 May 2023 
 
 
Confidential 
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Clinical Trial Protocol 
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
38 of 155 
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Clinical Trial Protocol 
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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Clinical Trial Protocol 
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
40 of 155 
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Clinical Trial Protocol 
EudraCT No.: 2019-003727-38 
 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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3 STUDY ADMINISTRATIVE STRUCTURE 
Coordinating Investigator 
 
Vall d'Hebron University Hospital 
Vall d' Hebron Institute of Oncology (VHIO) 
P. Vall d'Hebron 119-129 
08035 Barcelona. Spain 
Email: 
 
Phone: 
 
 
Sponsor 
Menarini Ricerche S.p.A. 
Clinical Sciences 
Via Sette Santi 1, 
50131 Florence, Italy 
 
 
Email: 
 
Phone: 
 
Fax: 
 
 
 
Email: 
 
Phone: 
 
 
 
Email: 
 
Phone:  
 
Fax: 
 
 
 
 
Email: 
 
Phone: 
 
Fax: 
 
 
 
 
Email: 
 
Phone: 
 
Fax:
 
Sponsor’s Pharmacovigilance Unit 
Laboratorios Menarini S.A. -Menarini Group 
Clinical Research 
C/ Alfons XII, 587 
08918 Badalona, Spain 
 
 
Email: 
 
Phone: 
  
Sponsor’s Pharmaceutical 
Manufacturer of the Study 
Treatment 
A. Menarini Research & Business Service GmbH  
Pharmaceutical Development Department 
Glienicker Weg 125 
12489 Berlin, Germany 
 

Clinical Trial Protocol 
EudraCT No.: 2019-003727-38 
 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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Email: 
 
Phone:  
  
Fax: 
 
 
 
Email:
 
Phone: 
 
Fax: 
 
 
Clinical Research Organisation 
IQVIATM 
3 Forbury Place, 
23 Forbury Road  
Reading 
RG1 3JH, United Kingdom 
 
 
Email: 
 
Phone: 
 
Details of all the laboratories will be provided in a separate Laboratory Manual. 

Clinical Trial Protocol 
EudraCT No.: 2019-003727-38 
 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
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4 TABLE OF CONTENTS 
 
1 
SIGNATURES ........................................................................................................................... 2 
2 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
2.1 
Schematic Design: Dose-Confirmation (Step 1) and Cohort-Expansion (Step 2) ............... 32 
 
 ................................................................................................................. 33 
 
 ..................................................................................................... 36 
 
 ............................................................................................. 38 
 
........................................................... 38 
 
 .............................................................. 39 
3 
STUDY ADMINISTRATIVE STRUCTURE ......................................................................... 41 
4 
TABLE OF CONTENTS ......................................................................................................... 43 
4.1 
Abbreviations ........................................................................................................................ 47 
5 
ETHICAL AND LEGAL ASPECTS ....................................................................................... 51 
5.1 
General Aspects .................................................................................................................... 51 
5.2 
Independent Ethics Committee and Legal Requirements ..................................................... 51 
5.3 
Patient Information and Declaration of Consent .................................................................. 51 
5.4 
Patient Insurance ................................................................................................................... 52 
5.5 
Documentation of Study-related Data and Record Retention .............................................. 52 
5.6 
Confidentiality ...................................................................................................................... 53 
5.7 
Protocol/Protocol Modifications ........................................................................................... 53 
5.8 
Study Commencement .......................................................................................................... 53 
5.9 
Patient’s Safety ..................................................................................................................... 54 
5.10  Data Property/Publication Policy ......................................................................................... 54 
5.11  Data Protection ..................................................................................................................... 55 
5.11.1 
General Principles on Personal Data Compliance ....................................................... 55 
5.11.2 
Acknowledgment ......................................................................................................... 55 
5.11.3 
Data Controllers and Data Processors .......................................................................... 55 
5.11.4 
Duties of the Parties involved in the Performance of the Study .................................. 56 
5.11.5 
Archiving of the Clinical Trial Master File and Patients’ Personal Data .................... 58 
5.11.6 
Data Breach .................................................................................................................. 59 
5.11.7 
Information Notice on Personal Data Protection and Pseudo-Anonymisation ............ 60 
5.11.8 
Genetic Data ................................................................................................................. 61 
5.11.9 
Transfer of Patients’ Data Outside the EU ................................................................... 63 
5.11.10  Exercise of Patients’ Data Privacy Rights ................................................................... 63 
5.11.11  Future Research............................................................................................................ 64 
6 
BACKGROUND INFORMATION ........................................................................................ 65 
6.1 
Colorectal Cancer ................................................................................................................. 65 
6.2 
Cetuximab in Colorectal Cancer ........................................................................................... 65 

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Study Code MEN1611-02 
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6.3 
PI3K Inhibitors in Cancer Therapy ...................................................................................... 68 
6.4 
PI3K Inhibitor and Cetuximab ............................................................................................. 69 
6.5 
Study Rationale ..................................................................................................................... 69 
6.6 
Investigational Medicinal Product: MEN1611 ..................................................................... 71 
6.6.1 
Physical, Chemical and Pharmaceutical Properties and Formulation .......................... 71 
6.6.2 
Non-Clinical Data ........................................................................................................ 71 
6.6.2.1 
Non Clinical Pharmacology ..................................................................................... 71 
6.6.2.1.1  Mechanism of Action – in vitro .......................................................................... 72 
6.6.2.1.2  In vivo Studies .................................................................................................... 72 
 
 ....................................................... 73 
6.6.2.3 
Toxicology and Safety Studies ................................................................................. 74 
6.6.3 
Clinical Experience ...................................................................................................... 76 
6.7 
Risk Benefit Assessment ...................................................................................................... 79 
6.7.1 
Risk Benefit Assessment for COVID-19 Pandemic .................................................... 83 
7 
STUDY OBJECTIVES ............................................................................................................ 85 
7.1 
Primary Objectives ............................................................................................................... 85 
7.2 
Secondary Objectives ........................................................................................................... 85 
7.3 
Exploratory Objectives ......................................................................................................... 85 
8 
INVESTIGATIONAL PLAN .................................................................................................. 86 
8.1 
Overall Study Design and Plan Description ......................................................................... 86 
8.2 
Selection of Study Population .............................................................................................. 87 
8.2.1 
Inclusion Criteria.......................................................................................................... 87 
8.2.2 
Exclusion Criteria ........................................................................................................ 89 
8.2.3 
Withdrawal of Patients from the Study or Discontinuation of the Study Treatment ... 91 
8.2.3.1 
Withdrawal from the Study ...................................................................................... 91 
8.2.3.2 
Withdrawal from the Study Treatment ..................................................................... 91 
8.2.4 
End of Study ................................................................................................................ 92 
8.3 
Identity of the Investigational Products ................................................................................ 92 
8.3.1 
Description of the Investigational Medicinal Products ................................................ 92 
8.3.2 
Packaging, Labelling and Storage ................................................................................ 92 
8.3.3 
Drug Accountability ..................................................................................................... 93 
8.3.4 
Destruction of the Study Treatment ............................................................................. 94 
8.4 
Treatments ............................................................................................................................ 94 
8.4.1 
MEN1611 ..................................................................................................................... 94 
8.4.2 
Cetuximab .................................................................................................................... 95 
8.4.3 
Treatment Compliance ................................................................................................. 95 
8.4.4 
Management of Toxicities due to MEN1611 and Dosage Modification ..................... 96 
8.4.5 
Management of Infusion-Related Reactions due to Cetuximab ................................ 105 

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Study Code MEN1611-02 
Final Version 5.0 
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8.4.6 
Management of Skin Toxicities due to Cetuximab .................................................... 107 
8.4.7 
Management of Other Cetuximab-Related Adverse Events ...................................... 110 
8.4.8 
Prohibited and Concomitant Medications .................................................................. 111 
8.4.9 
Dietary and Lifestyle Restrictions .............................................................................. 112 
8.5 
Study Procedures and Assessments .................................................................................... 112 
8.5.1 
Study Procedures........................................................................................................ 112 
8.5.2 
Sample Handling and Shipping Management ............................................................ 121 
8.5.3 
 ........................................................... 121 
8.5.4 
Safety Assessment ..................................................................................................... 122 
8.5.4.1 
Medical History ...................................................................................................... 122 
8.5.4.2 
Physical Examination and Vital Signs ................................................................... 122 
8.5.4.3 
Weight measurement .............................................................................................. 123 
8.5.4.4 
Body Surface Area ................................................................................................. 123 
8.5.4.5 
Performance Status Evaluation .............................................................................. 123 
8.5.4.6 
Clinical Laboratory Evaluation .............................................................................. 124 
8.5.4.7 
12-Lead Electrocardiogram .................................................................................... 126 
8.5.5 
Study Endpoints ......................................................................................................... 126 
8.5.5.1 
Primary Endpoints .................................................................................................. 126 
8.5.5.2 
Secondary Endpoints .............................................................................................. 127 
8.5.5.3 
Exploratory Endpoints ............................................................................................ 127 
8.6 
Adverse Event Definitions, Monitoring/Recording and Management ............................... 128 
8.6.1 
Definitions .................................................................................................................. 128 
8.6.1.1 
Adverse Event ........................................................................................................ 128 
8.6.1.2 
Drug Relationship................................................................................................... 128 
8.6.1.3 
Treatment-Emergent Adverse Events .................................................................... 129 
8.6.1.4 
Adverse Drug Reactions ......................................................................................... 129 
8.6.1.5 
Seriousness ............................................................................................................. 130 
8.6.1.6 
Adverse Drug Reaction Expectedness ................................................................... 131 
8.6.1.7 
Serious Unexpected Adverse Reaction .................................................................. 131 
8.6.2 
Monitoring and Recording of Adverse Events .......................................................... 131 
8.6.3 
Management of Serious Adverse Events ................................................................... 132 
8.6.3.1 
Reporting Duties of the Investigator ...................................................................... 132 
8.6.3.2 
Reporting Duties of the Sponsor ............................................................................ 133 
8.6.4 
Management of Non-Serious Adverse Events and/or Laboratory Abnormalities ..... 134 
8.6.5 
Management of Pregnancy Exposure Cases .............................................................. 135 
8.6.6 
Management of Misuse and Overdose Cases ............................................................ 135 
8.6.7 
Periodic Safety Reporting .......................................................................................... 136 
8.6.7.1 
Annual Safety Reporting (DSUR or IND Annual Report) ..................................... 136 
8.6.7.2 
Periodic Line-listings Safety Reporting ................................................................. 136 
8.6.8 
Safety Issues other than SUSARs .............................................................................. 136 

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8.6.9 
Breaking of the Randomisation Code ........................................................................ 137 
8.6.10 
Serious and Non-Serious Adverse Events Follow-up ................................................ 137 
8.7 
Data Safety Committee and Safety Monitoring.................................................................. 137 
8.8 
Blinded Independent Review Committee (BIRC) .............................................................. 138 
9 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...................... 139 
9.1 
Determination of Sample Size ............................................................................................ 139 
9.2 
Analysis Populations .......................................................................................................... 139 
9.3 
Statistical Analysis ............................................................................................................. 140 
9.3.1 
Descriptive Statistics .................................................................................................. 140 
9.3.2 
Pharmacokinetic Analysis .......................................................................................... 140 
9.3.3 
Efficacy Analysis ....................................................................................................... 141 
9.3.4 
Safety Analysis .......................................................................................................... 141 
9.3.5 
Data Imputations ........................................................................................................ 141 
9.4 
Protocol Violations and Data Review Meeting .................................................................. 141 
9.5 
Statistical Analysis Plan ..................................................................................................... 141 
10 
DATA QUALITY MANAGEMENT .................................................................................... 142 
10.1  Data Collection ................................................................................................................... 142 
10.1.1 
Electronic Case Report Form ..................................................................................... 142 
10.1.2 
Interactive Web-response System .............................................................................. 143 
10.1.3 
Patient Diary .............................................................................................................. 143 
10.1.4 
Central Laboratory/Examination Data ....................................................................... 143 
10.1.5 
Tumour Images Collection......................................................................................... 143 
10.1.6 
Data Capture Systems Versions and Validation Documentation ............................... 144 
10.2  Clinical Data Management ................................................................................................. 144 
10.3  Source Data ......................................................................................................................... 144 
10.4  Quality Control/Quality Assurance .................................................................................... 145 
10.4.1 
Study Monitoring ....................................................................................................... 145 
10.4.2 
Quality Assurance ...................................................................................................... 145 
11 
PREMATURE TERMINATION OF THE WHOLE STUDY .............................................. 146 
12 
END OF CLINICAL STUDY AND ARCHIVING .............................................................. 147 
12.1  Archiving of Electronic Documentation/Data .................................................................... 147 
13 
APPENDICES ....................................................................................................................... 148 
 ............... 148 
 
.................................................................................................................................... 151 
14 
REFERENCES....................................................................................................................... 152 
 

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4.1 Abbreviations 
A.MRBS 
A. Menarini Research & Business Service GmbH 
ADL 
Activities of daily living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AKT 
v-Akt murine thymoma viral oncogene homolog 
ALP 
Alkaline phosphatase 
ALT(SGPT) 
Alanine aminotransferase 
a/m 
Advanced or metastatic 
ANC 
Absolute neutrophil count 
AOSE 
Analysis of Similar Events 
AST(SGOT) 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
ß-HCG 
Beta human chorionic gonadotropin 
BA 
Bioavailability 
BID 
Bis in die, twice a day, twice daily 
BIRC 
Blinded Independent Review Committee 
BP 
Blood pressure 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CA 
Competent authority 
CA19-9 
Carbohydrate antigen 19-9 
CABG 
Coronary artery bypass grafting 
CEA 
Carcinoembryonic antigen 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CIOMS 
Council for International Organization of Medical Sciences 
CL/F 
Apparent systemic clearance 
Cmax 
Maximum observed plasma concentration 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CRO 
Contract research organisation 
CT 
Computed tomography 
CTC 
Circulating tumour cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumour deoxyribonucleic acid 
CV% 
Coefficient of variation 
CYP 
Cytochrome 
CYP1A 
Cytochrome P450, family 1, subfamily A 

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CYP3A 
Cytochrome P450, family 3, subfamily A 
DAP 
Data analysis plan 
DCR 
Disease control rate 
DDI 
Drug-drug interaction 
DLP 
Data lock point 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DPO 
Data protection officer 
DRM 
Data review meeting 
DSC 
Data Safety Committee 
DSUR 
Development Safety Update Report 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FOLFIRI 
Folinic acid, fluorouracil and irinotecan 
FPG 
Fasting plasma glucose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GM 
Geometric mean 
H1 
Histamine-1 
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 
HEENT 
Head, eyes, ears, nose and throat 
HER2 
Human epidermal growth factor receptor-2 
hERG 
Human Ether-à-go-go-related gene 
HIV 
Human immunodeficiency virus 

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HNSCC 
Head and neck squamous cell carcinoma 
HR 
Hazard ratio 
HRT 
Hormone-replacement therapy 
IB 
Investigator´s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICSR 
Individual Case Safety Report 
IEC 
Independent ethics committee 
ID 
Identification 
IGF 
Insulin growth factor 
ILD 
Interstitial lung disease 
IMP 
Investigational Medicinal Product 
INR 
International normalised ratio 
IRB 
Institutional review board 
IV 
Intravenous(ly) 
IWRS 
Interactive web-response system 
LDH 
Lactate dehydrogenase 
MAF 
Mutated allele frequency 
mCRC 
Metastatic colorectal cancer 
MCV 
Mean corpuscular volume 
moAbs 
Monoclonal antibody 
mOS 
Median overall survival 
mPFS 
Median progression-free survival 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multigated acquisition 
N 
Number of non-missing observations 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
ORR 
Overall response rate 
OS 
Overall survival 
p-AKT 
Phosphorylated AKT 
PDGFR 
Platelet derived growth factor 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PIK3CA 
Phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene 
PI3K 
Phosphatidylinositol/phosphoinositide 3-kinase 
PIP3 
Phosphatidylinositol (3,4,5)-trisphosphate 
PK 
Pharmacokinetic/s 

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PR 
Partial response 
PRP 
Platelet-rich plasma 
PS 
Performance status 
PTEN 
Phosphatase and tensin homolog 
QA 
Quality assurance 
QD 
Quaque die, once a day, once daily 
QoL 
Quality of life 
QTc 
QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
RP2D 
Recommended phase 2 dose 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SD 
Stable disease 
SDSM 
Study Drug Safety Manager 
SDSU 
Study Drug Safety Unit 
SE 
Standard error 
SmPC 
Summary of Product Characteristics 
SMP 
Safety Management Plan 
SOP 
Standard operating procedure 
SPF 
Sun Protection Factor 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal plasma half-life 
TEAE 
Treatment-emergent adverse event 
TGFα 
Transforming growth factor alpha 
TMF 
Trial master file 
ULN 
Upper limit of normal 
US(A) 
United States (of America) 
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 
WT 
Wild-type 
Ka 
Absorption rate constant 

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5 ETHICAL AND LEGAL ASPECTS 
5.1 General Aspects 
This study will be carried out in compliance with the study protocol, the recommendations on biomedical 
research on human patients 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, monitoring and 
termination as well as project management). The Sponsor will perform study planning and preparation, 
medical monitoring and safety management, medical writing and quality management data management 
and statistical analysis. 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. 
5.2 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.  
5.3 Patient Information and Declaration of Consent 
Before any study-related procedures may be performed, informed consent must be obtained from the 
patient 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 patient. 

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In the patient information leaflet, patients 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. 
Patients 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 patient 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 
patient 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 ICF is signed 
by all patients subsequently entered in the study and those currently in the study, before the changes take 
effect on their participation in the study. Patients who do not sign the new ICF need to be terminated 
from the study participation. 
5.4 Patient Insurance 
For patients 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 
patients 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). 
5.5 Documentation of Study-related Data and Record Retention 
It is the responsibility of the Investigator to document all study-related data for each patient 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 patient in the clinical study, including the study assessments (patient 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. 
5.6 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 patient’s confidentiality, all data collected by the Investigator will be recorded 
pseudonymously in the eCRF. Patient’s data will be identified by a unique patient 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. Patient 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. 
5.7 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 patients, or to change the interpretation of the scientific 
documents on which the trial is based or the scientific validity of the study results, significantly alter the 
nature of the management or conduct of the study, or impair the quality or safety of the investigational 
drugs, or if they are otherwise significant, the IRB/IECs and the CAs in the participating countries have 
to approve these amendments before implementation.  
5.8 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.  

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5.9 Patient’s Safety 
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 patients against any immediate hazard. The CAs and IRB/IECs will be informed 
forthwith about these new events and the measures taken. 
5.10 Data Property/Publication Policy 
All data generated in the study (e.g. eCRFs, patient 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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5.11 Data Protection 
5.11.1 
General Principles on Personal Data Compliance 
All clinical study 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 patients 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 patients’ 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 

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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 
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 patients' personal data (i.e. patients' data), including their biological samples, 
will be carried out in full respect of the provisions of the information notices submitted to patients, 
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 patients 
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 patient’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 patients’ 
personal data are stored shall be placed in a restricted-access area, accessible only to those 
individuals who need to retrieve the patients’ 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 patients’ 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 patients’ personal data (i.e. name, surname, etc.) with their respective 
“Patient 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 patients' 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 patients 
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 patients from the data pertaining to the study by linking results to a an 
alphanumerical code “Patient Identification (ID)”, whose format shall not make it possible to identify 

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the patient directly or indirectly, so 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.  
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 study. Biological 
samples and any other examination (e.g. X-ray, electrocardiogram [ECG]) shall bear Patient ID, and 
in no case will they bear other information that may lead to the direct or indirect identification of the 
patient, especially when, in accordance with this protocol, samples shall be forwarded and shared 
outside the clinical site (e.g. in case of centralized reading or local laboratory analysis).  
(v) 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 afore mentioned measures shall be provided by the 
Sponsor, the site and/or the CRO to the CAs (including data protection authorities) and IRB/IECs 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 patients’ 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 Patients’ 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 
patients’ personal data, for at least 25 years after the end of the clinical study. However, medical 
records shall be archived in accordance with the national laws of the country where the study is 
performed. The patient code pairing list (i.e. the list that where the Patient ID is linked to the patients’ 
identification data such as name and surname), shall be archived care of the Principal Investigator. 
The content of the clinical TMF shall be archived in a way that ensures that it is readily available and 
accessible, upon request, to the CAs. 
Any transfer of ownership of the content of the clinical TMF 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. 

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The media used to archive the content of the clinical TMF shall be such that the content remains 
complete and legible throughout the period referred to in the first paragraph. Any modification to the 
content of the clinical TMF shall be traceable. 
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 patients’ 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 (DPO), 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, Sponsor and 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 patients enrolled within the EU, 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 patients; 
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 patients. 
5.11.7 
Information Notice on Personal Data Protection and Pseudo-
Anonymisation 
Prior to patients’ enrolment in the study, the Principal Investigator and/or the site (including their 
personnel) shall provide each patient 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 his/her 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 patients about:  

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(i) The applicable data protection legislation; 
(ii) What kind of data shall be collected during the study listing them in detail or by category; 
(iii) The purpose of data processing (e.g. for performance of the study and/or for pharmacovigilance 
purposes and/or registration of new drugs) 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 further medical and scientific research purposes 
such as studies aimed at evaluating new medicine; studies which compare the data of this study with 
other sources, etc.; 
(vi) The pseudonymisation procedure and scope; 
(vii) Who can access patients’ data and under what circumstances (Principal Investigator and site for 
patient management along the study, Sponsor and its vendors for collection and analysis purposes, 
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 Sections 5.11.4 and 5.11.5 above, including 
the storage of the biological sample; 
(ix) To which entities/countries outside the EU patients’ data will be transmitted (including but not 
limited to the USA; the complete list will be available upon request – see Section 5.11.9); 
(x) Patients’ 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 DPO contacts (dpo@menarini.com); 
(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; 

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genetic data shall be processed pursuant to the applicable pharmacovigilance laws and 
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 will be the following as 
defined in Section 8.5.1 and Section 8.5.2. 
 Without prejudice to applicable laws and regulations, except for data and results as per 
Section 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 patients’ identification data separated from biological materials and 
genetic information are reported in Section 5.11.4 and Section 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, 
patients’ identities will be disclosed only when strictly necessary (e.g. to prevent a physical 
prejudice).  

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 Genetic and medical data will be processed separately from any other personal data that can 
identify the patients directly. 
 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 his/her 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 Patients’ Data Outside the EU  
The study performance entails transferring patients’ 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, and patients’ specific consent. Examples of non EU countries/entities including but not limited 
to the USA. The complete list will be available upon request.  
5.11.10 Exercise of Patients’ Data Privacy Rights  
Each study patient 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 patient 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 patient; 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 patient 
has the right to lodge a complaint with his/her local supervisory authority and/or to notify to the DPO 
any use of his/her personal data the patient regards as inappropriate.  
Each study patient is free to withdraw at any time from the study. In such case, each study patient 
may ask the Sponsor, the Site, the Principal Investigator, the central laboratories, the CRO to 
destroy/delete his/her personal data (including his/her biological samples [see Section 8.5.2] unless 
they have been permanently anonymised), thus preventing any further processing or analysis of 

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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 apply. Please refer to Section 5.11.8. 
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´s DPO by email 
at dpo@menarini.com 
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 patients within the above mentioned 
deadline. 
5.11.11 Future Research  
With patients' 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 patients’ 
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, patients’ data will be processed, anonymized and 
transferred abroad, and may be shared with future research partners –in most cases this will prevent 
patient identification; however, in the unlikely event patients’ 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 
6.1 Colorectal Cancer 
Colorectal Cancer (CRC) is one of the most commonly diagnosed cancer worldwide and a leading 
cause of death. In the year 2012, the death toll was above 693 000 and there have been 1.4 million 
newly diagnosed cases worldwide (1-5). Up to 50% of these newly diagnosed patients have metastatic 
disease (2-3). These patients have an overall survival (OS) reported to be about 30 months in average. 
While this is a great improvement to the state 20 years ago (OS = 6 months), the prognosis for patients 
with metastatic CRC (mCRC) remains poor (1-3, 5). Besides a selected number of local therapies the 
vast majority of patients with mCRC receive systemic treatment with chemotherapeutic agents such 
as irinotecan, oxaliplatin, fluropyrimidines, in combination with targeted monoclonal antibodies, such 
as cetuximab, bevacizumab, panitumumab, aflibercept, and ramucirumab considered to be the 
currently accepted standard of care for first or second line treatment. Regorafenib and TAS-102 are 
currently indicated as monotherapy in the refractory setting. Pembrolizumab, nivolumab and 
ipilimumab are further options in patients with metastatic mismatch repair deficient CRC. 
However, the optimal chemotherapeutic regimen beyond second line treatment remains unclear and 
more than 30% of mCRC patients receive 3 or more lines of therapy (2-5). 
6.2 Cetuximab in Colorectal Cancer 
Cetuximab is a chimeric IgG1 monoclonal antibody (moAbs) directed against the extracellular 
domain of epidermal growth factor receptor (EGFR). The EGFR is a member of the tyrosine kinase 
family of growth factor receptors with tyrosine kinase activity. It possesses an extracellular domain, 
which offers a ligand-binding site for epidermal growth factor (EGF) and for transforming growth 
factor alpha (TGF), a transmembrane domain and an intracellular protein tyrosine kinase element. 
The intracellular domain of EGFR is activated upon ligand binding, which triggers the EGF-mediated 
tyrosine kinase signal transduction pathway and promotes cellular growth, division and survival. 
EGFR antibodies block the ligand-binding site to prevent its linkage with TGF and EGF resulting 
in interruption of this pathway in order to reduce cellular proliferation (6). 
Cetuximab revealed in numerous Phase II and III clinical studies a significant improvement in terms 
of progression-free survival (PFS), OS, response rate (RR), and quality of life (QoL), among different 
lines of treatment, both alone and in combination with chemotherapy (1). 
Expression or up-regulation of the EGFR gene happen in around 80% of colorectal cancers and are 
connected with metastatic risk. Nevertheless, the presence of an EGFR mutation is not linked to the 
efficacy of EGFR inhibition. In the last years, several findings directed to the identification of other 

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predictive biomarkers: Initially KRAS, then NRAS and HRAS as genes that might affect the efficacy 
of EGFR moAbs. 
The CRYSTAL study was the first one to evaluate the combination of cetuximab and folinic acid, 
fluorouracil and irinotecan (FOLFIRI) as first line treatment in metastatic CRC: Patients with an 
EGFR positive tumour, were randomized to receive cetuximab plus FOLFIRI or FOLFIRI alone. The 
combination showed an improvement in PFS (8.9 months vs 8.0 months; hazard ratio (HR) 0.85, 95% 
confidence interval (CI) 0.72-0.99; p=0.0048). In terms of RR, cetuximab plus FOLFIRI reached a 
significant advantage in comparison to FOLFIRI alone (RR 46.9% vs 38.7; P=0.004). There was no 
significant difference in OS between the two groups: 19.9 months vs 18.6 months. The retrospective 
subgroup analysis according to KRAS mutational status indicated that benefit of cetuximab was 
limited to patients with KRAS wild-type tumours: Median PFS (mPFS) with cetuximab-FOLFIRI and 
FOLFIRI alone were 9.9 months and 8.7 months, respectively, in the wild type-KRAS population and 
7.6 and 8.1 months, respectively, in the mutant-KRAS population (HR 0.68, p=0.017). In patients with 
wild type KRAS tumours, the RR in the cetuximab-FOLFIRI group was 59.3% and in the FOLFIRI 
group 43.2% (OR, 1.91; 95% CI, 1.24 to 2.93). In mutated-KRAS tumours, RR was 36.2% in the 
cetuximab–FOLFIRI group and 40.2% in the FOLFIRI group (OR, 0.80; 95% CI, 0.44 to 1.45) (7-
8). 
When cetuximab is used as single agent in unselected patients with chemotherapy-refractory mCRC, 
it achieved a RR of only 10% (9-10). As reported by Karapetis et al. in patients with wild-type KRAS 
tumours, treatment with cetuximab significantly improved median OS (mOS) (9.5 vs. 4.8 months; 
HR 0.55; 95% CI, 0.41 to 0.74; P<0.001) and mPFS (3.7 months vs. 1.9 months; HR 0.40; 95% CI, 
0.30 to 0.54; P<0.001) when compared to supportive care alone. In the cetuximab group, the RR 
among patients with wild-type KRAS tumours was 12.8%, only one patient with a mutated KRAS 
tumour (1.2%) had a response (11). 
All reported findings from post-hoc, retrospective and meta-analyses for anti-EGFR, confirmed a 
negative predictive value of KRAS exon 2 mutations (12). 
Furthermore, a new confirmation from the PRIME study with panitumumab indicated that mutations 
(other than those in KRAS exon 2) in exons 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS (expanded 
RAS analysis) predict a lack of response to EGFR-monoclonal antibodies (13). In a retrospective 
analysis of the FIRE-3 study, additional RAS mutations were detected, observing an improvement in 
mOS (33.1 versus 28.7 months) in patients with expanded RAS wild-type tumours treated with 
cetuximab compared with those with KRAS exon 2 wild-type tumours treated with cetuximab (14). 
KRAS and NRAS mutations have been identified as biomarkers of resistance to anti-EGFR antibodies 
and cetuximab and panitumumab are currently recommended for mCRC patients expressing wild-

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type RAS representing a standard of care in the first-line setting with a particular benefit for patients 
with left-sided tumours (1). 
Cetuximab has also an important role in second or later-line of treatment as single agent or in 
combination with irinotecan after progression to a previous chemotherapy. In third line and beyond, 
refractory patients are also usually treated with available agents that offer very limited opportunities 
of clinical efficacy. 
Recent findings express that particular patients cannot be considered lastingly resistant to biologic 
and cytotoxic agents and conversely some tumours may maintain sensitivity to cetuximab or recover 
sensitivity after a treatment break from this drug (5). 
Based on these observations, clinical studies have been conducted to investigate the role of 
rechallenge as new therapy choice for refractory metastatic colorectal cancer. 
In a multicentre retrospective analysis conducted by Santini et al. 39 patients, previously progressed 
on cetuximab plus irinotecan-based therapy, were rechallenged with cetuximab plus irinotecan after 
a treatment pause during which they were treated with non-irinotecan-based chemotherapy. The 
mPFS was 6.6 months (95% CI, 4.1%-9.1%). Overall RR (ORR) with cetuximab plus irinotecan 
rechallenge was 53.8% (95% CI, 39.1%-63.7%) and included nineteen partial responses (48.7%) and 
two complete responses (5.1%). Stable disease was reached in 35.9% of patients, for a total disease 
control rate of 89.7% (15). 
Similarly, in the E-Rechallenge study, 33 patients with KRAS wild-type (WT) mCRC, refractory to 
previous fluoropyrimidines, oxaliplatin, irinotecan, cetuximab, and bevacizumab and in whom 
previous treatment with cetuximab was effective in any earlier line, were rechallenged with 
cetuximab and oxaliplatin. Overall, 15.6% (95% CI, 5.3%-32.7%) of the patients had a partial 
response, 40.6% (95% CI, 23.6%-57.6%) had stable disease, and 43.8% (95% CI, 26.4%-62.3%) had 
a progressive disease. The mPFS was 88 days and OS was 262 days (16). 
In the recent prospective Phase II CRICKET study (Cetuximab Rechallenge in Irinotecan-pretreated 
mCRC, KRAS, NRAS and BRAF Wild-type Treated in 1st Line With Anti-EGFR Therapy), 28 
patients with KRAS WT metastatic colon cancer were rechallenged with third-line cetuximab and 
irinotecan. ORR was 23% (95% CI, 10%-40%) with disease control rate of 54% (95% CI, 36%-70%) 
and the study met its primary end point. Patients with RAS WT circulating tumour deoxyribonucleic 
acid (ctDNA) had significantly longer PFS than those with RAS mutated ctDNA (4.0 vs 1.9 months; 
HR 0.44; 95% CI, 0.18-0.98) (17). 
In all these studies, findings suggest a clinical benefit and no signal for increased toxicity. The 
selection may be improved by rechallenging patients who do not develop KRAS mutations (17). 
For this reason, retesting RAS status beyond progression to first-line cetuximab plus chemotherapy 
may be a useful approach to better identify candidates for cetuximab rechallenge. Liquid biopsy offers 

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a non-invasive method for the recognition and analysis of ctDNA and might satisfy the retesting 
requisites. 
6.3 PI3K Inhibitors in Cancer Therapy 
Phosphoinositide 3-kinases (PI3Ks) belonging to the family of heterodimeric lipid kinases and 
consisting of a regulatory and a catalytic subunit control most key regulatory factors in many cellular 
processes including cell cycle, survival, proliferation and differentiation, metabolism, motility, 
migration and genomic instability (18-21). 
PI3K is activated by EGFR, insulin growth factor (IGF-1R), several receptor tyrosine kinases, human 
EGFR 2 (HER2), and platelet derived growth factor (PDGFR). Once activated PI3K mediates signals 
to a multitude of downstream effectors such as v-akt murine thymoma viral oncogene homolog 
(AKT) and mammalian target of rapamycin (mTOR) as well as promoting additional cancer-
benefitting factors such as recruitment of inflammatory cells and angiogenesis. In most cases of 
cancer PI3K shows mutations that lead to hyperactivity, even if not the case the downstream effector 
phosphatidylinositol-3,4,5-trisphosphate (PIP3) is constitutively elevated. Mutations in the 
phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene (PIK3CA) encoding the catalytic 
isoform p110α of PI3K are frequently observed in several cancer types. These cancer types are breast, 
glioblastoma, gastric, ovary, lung and CRC, where it can be detected in 10–20% of CRC patients. 
Most of these mutations (80%) are restricted to hot spots in exon 9 and exon 20 of PIK3CA. In 
addition to this activating mutation of PI3K another often observed oncogenic mutation is that of 
PTEN (phosphatase and tensin homolog deleted from chromosome 10). PTEN encodes the major 
PIP3 phosphatase which is the most important antagonistic factor in the PI3K signalling cascade and 
correlates with a poor outcome in CRC patients. The PI3K pathway is also upregulated in cancer cells 
that show no genomic alterations in PI3K and PTEN as other lesions are present activating the PI3K 
pathway such as activated tyrosine kinases, RAS, AKT; loss of LKB1 (STK11), INPP4B or TSC (18-
21). 
The combination of PIK3CA mutation and RAS wild-type CRC has been reported to correlate with a 
negative prediction of response to anti-EGFR treatment (21). 
 
 

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6.4 PI3K Inhibitor and Cetuximab 
Preclinical data suggested that combination therapies directed against both PI3K and EGFR pathways 
might improve responses in head and neck squamous cell carcinoma (HNSCC) (22-24). Given these 
promising data, several clinical studies assessing cetuximab in combination with inhibitors of PI3K 
have been opened in HNSCC. 
In a Phase I, dose-finding study, eleven patients were enrolled to determine the safety, maximum 
tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumour activity of PX-866, a 
phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with advanced CRC or 
HNSCC. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. No dose limiting toxicities 
were observed. Best responses in 9 evaluable patients were: 4 partial responses (44.4%), 4 stable 
disease (44.4%), and 1 disease progression (11.1%). The mPFS was 106 days (25). Unfortunately, a 
Phase II study, combining PX-866 with cetuximab failed to achieve improved PFS or OS compared 
to cetuximab alone, suggesting that a better understanding of the molecular mechanisms of action 
that drive response to PI3K and EGFR therapies is essential (26). 
6.5 Study Rationale 
CRC is a heterogeneous disease in which genomic analysis provides data on the presence of activating 
mutations in the KRAS, NRAS and others genes. This approach offers criteria for the selection of 
patients for the anti-EGFR therapy. KRAS and NRAS mutations have been identified as biomarkers 
of resistance to anti-EGFR antibodies and they are currently recommended for mCRC patients 
expressing WT RAS (1). However, only a small percentage of mCRC patients are sensitive to anti-
EGFR therapy and even the subgroup of patients who initially respond, finally become refractory in 
around 3-18 months (secondary resistance). 
Primary and acquired resistance has been shown to be the principal cause of the failure of anti-EGFR 
drugs: RAS mutations only account for nearly 35%-50% of non-responsive patients. Recent studies 
have detected mutations in several genes in the EGFR signalling pathway, such as BRAF, PIK3CA 
and PTEN (27-28). 
Mutations of PIK3CA are described in around 10-18% of mCRC patients and can coexist with both 
RAS (concomitant KRAS mutation about 50%) and BRAF mutations (29). Their prevalence in CRC 
increases continuously from the rectum to the cecum, according the colorectal continuum model. 
More than 80% of PIK3CA mutations occur in exon 9 or exon 20 and patients who present double 
mutations have a worse prognosis. The RAS/RAF/MEK/ERK and PI3K/AKT/PTEN signalling 
pathways are strictly connected. EGFR in fact, also triggers the PIK3CA/PTEN signalling cascade 
and both can be blocked by EGFR inhibitors, causing tumour cell apoptosis. 

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In mCRC, clinical and preclinical studies have tried to identify PIK3CA mutations as a predictor of 
lack of response to anti-EGFR therapy. Biochemical studies showed that exon 9 mutations induces 
gain of function through RAS-GTP binding, while exon 20 mutations seems to act independently by 
RAS-GTP interaction (30-31). In a retrospective analysis of 110 mCRC patients treated with 
cetuximab or panitumumab, a statistically significant association between PIK3CA mutations and 
primary resistance to anti-EGFR therapies was found in the population with KRAS WT tumours (32). 
A large retrospective analysis conducted by the European consortium investigated the effect of 
PIK3CA mutations on the response to cetuximab: In the KRAS WT population, carriers of PIK3CA 
exon 20 mutations showed significantly lower response rates than carriers of WT PIK3CA. Exon 9 
mutations revealed no significant effect and this result suggests its secondary role on cetuximab 
efficacy (27). Two additional meta-analyses have highlighted that only PIK3CA exon 20 mutations 
were associated with a lack of response to anti-EGFR moAbs in terms of ORR, PFS, and OS in WT 
KRAS mCRC population (33-34). Overall, it appears clear that PIK3CA exon 9 and exon 20 mutations 
differ in their predictive role. 
In summary, over the past few years clinical studies have showed that aberrant biomarkers, other than 
RAS mutations, such as BRAF mutations, PIK3CA mutations, PTEN loss and others, result in 
resistance to anti-EGFR therapy mainly through constitutive activation of EGFR downstream 
signalling pathways, irrespective of EGFR blockade. These findings have led to target BRAF mutant, 
HER2-amplified and microsatellite-unstable CRCs, demonstrating important benefit (35). Due to the 
presence of oncogenic activation of the PI3K/AKT/PTEN cascade in several cancers and its relevance 
in crucial cellular functions, it is reasonable to assume that hitting the PI3K pathway might represent 
a strategic focus for the treatment of mCRC. Currently, there are no definite therapies for PIK3CA 
mutated metastatic colorectal cancer patients and this population is treated with available anticancer 
agents. 
PIK3CA mutations have also been identified as mechanisms of secondary resistance in tumour 
samples from patients relapsing after EGFR-targeted therapies but in general, the acquisition of 
secondary mutations has not an established role in resistance to anti-EGFRs in mCRC.  
WT RAS tumours at baseline, after an initial response, can develop resistance to anti-EGFR drugs 
shifting to mutated status and resulting in progression disease. This is due to the intratumoural 
heterogeneity that determines a reduction or destruction of WT cells and a progressive proliferation 
of RAS-mutant clones. After a further line without anti-EGFR drugs, cells may regain sensitivity to 
cetuximab.  
Based on these biological evidences some recent studies (such as Cricket, E-Rechallenge and Santini 
studies) suggest that the reuse of cetuximab as continuation or rechallenge, after progression to a 

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previous anti-EGFR containing regimen should be considered an effective and tolerable option in 
patients with a good performance status, in later line treatment (15-17, 36). 
The current study is designed in light of the fact that rational combination of cetuximab and the PI3K 
inhibitor MEN1611, in the setting described above should block each possible signalling cascade and 
represent an optimal approach to overcome anti-EGFR therapy resistance. 
6.6 Investigational Medicinal Product: MEN1611 
6.6.1 
Physical, Chemical and Pharmaceutical Properties and Formulation 
MEN1611 or 5-(7-Methylsulfonyl-2-morpholin-4-yl-6,7-dihydro 5Hpyrrolo[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 capsule for oral administration.  
6.6.2 
Non-Clinical Data 
6.6.2.1 
Non Clinical Pharmacology 
MEN1611 is a potent, selective Class I PI3K inhibitor with a novel structure. In cell-free assays, 
MEN1611 selectively inhibited Class I PI3Ks but showed less inhibition of Class II PI3Ks (C2α and 
C2β), Class III PI3K (Vps34) and PI3K-related protein kinases (deoxyribonucleic acid [DNA]-PK 
and mTOR). In in vitro anti-proliferation assays, MEN1611 exhibited cell growth inhibition against 
a wide variety of cancer cells that are addicted to PI3K/AKT pathway activation. Consistent with the 
in vitro anti-proliferation activity, MEN1611 exhibited potent anti-tumour efficacy in a variety of 
human xenograft models with PI3K/AKT pathway-activated tumours with daily oral administration. 
In the grafted tumours, a pharmacodynamic response was confirmed by the reduction of 
phosphorylated-v-akt (p-AKT). 
Moreover, in combination with current standard therapies, MEN1611 showed significant 
enhancement of anti-tumour efficacy with good tolerability. The potential combination agents with 
good compatibility include not only molecular targeted agents (e.g. trastuzumab, erlotinib and 
bevacizumab) but also cytotoxic agents (e.g. cisplatin, temozolomide and paclitaxel). 
Moreover, the rat and cynomolgus monkey were chosen for in vivo safety studies based on their 
similarity to human regarding their drug metabolism pattern in vitro and suitable kinetic data, 
including good oral bioavailability and demonstration of pharmacological activity. 
 
 

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6.6.2.1.1 
Mechanism of Action – in vitro 
In cell-free enzyme assays, MEN1611 inhibited Class I PI3Ks, particularly, PI3Kα and its mutants, 
with half maximal inhibitory concentration (IC50) of 14 nmol/L (α), 6.7 nmol/L (α, E542K), 
6.7 nmol/L (α, E545K) and 5.6 nmol/L (α, H1047R). The effects of MEN1611 on proliferation of 
cancer cells with activated PI3K/AKT pathways were investigated demonstrating that MEN1611 
potently inhibited proliferation of cancer cells with PI3Kα mutations at each of 3 hot spots, E542, 
E545 and H1047 and with PTEN genetic inactivation. In agreement, MEN1611 significantly reduced 
phosphorylation of AKT, a key downstream mediator of PI3K, at the T308 and S473 residues, in a 
dose-dependent manner. In addition, phosphorylation of downstream factors, including proline rich 
AKT substrate 40, p70 ribosomal S6 protein kinase, S6, GSK3β and FoxO1/3a, was also suppressed 
in MEN1611-treated cells, suggesting significant inhibition of the PI3K/AKT pathway by MEN1611. 
6.6.2.1.2 
In vivo Studies 
Consistent with in vitro observations, MEN1611 also demonstrated potent anti-tumour efficacy in 
PI3K/AKT pathway-activated xenograft models. Daily oral administration of MEN1611 significantly 
reduced volume of the grafted tumours of a variety of tumour types with activated PI3K/AKT 
pathway including breast, ovarian, prostate, endometrial and gastric cancers. 
Moreover, the therapeutic potential of MEN1611 in combination with current standard therapeutics, 
including molecular targeted agents and cytotoxics was demonstrated in the NCI-H292 (non-small 
cell lung cancer in combination with erlotinib), in the HCT116 model of colon cancer in combination 
with bevacizumab and in the SK-OV-3 ovarian cancer model in combination with paclitaxel.  
The antitumour efficacy of MEN1611 in combination with cetuximab was investigated in two 
xenografts models WT for KRAS and mutated in BRAF (p.V600E), harboring mutations in the 
PIK3CA. MEN1611 alone and in combination with cetuximab showed a significant tumour volume 
inhibition. The combination showed significant tumour growth delay. No toxic effects were observed 
in terms of body weight change and clinical signs.  
The effect of MEN1611in CRC was further evaluated in a KRAS and PIK3CA genetic background 
using two patient-derived xenografts, both harbouring a PIK3CA mutation and a p.Q61H or p.G12D 
mutation in the KRAS gene. MEN1611 in combination with bevacizumab showed no synergistic 
activity. The combination showed growth delay only and no evidence of long lasting anti-tumour 
activity. 
 
 

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6.6.2.3 
Toxicology and Safety Studies 
Single-dose toxicity was evaluated in the safety pharmacology studies in rats and cynomolgus 
monkeys, and the in vivo micronucleus test in rats. Only slight toxic effects on digestive system (loose 
stool and vomiting) were observed at highest doses in rats and cynomolgus monkeys. 
In a Good Laboratory Practice (GLP), 4-week, oral, repeat-dose toxicity study (dose levels: 0, 0.05, 
0.25, 1.25 and 6.25 mg/kg/day) in mature rats (14 weeks old at dose initiation), the key toxicological 
findings are classified into the following six groups: (1) Hyperglycaemia-related changes includes 
increases in glucose (blood and/or urinary glucose with and without blood insulin) and hypertrophy 
of islet cells in the pancreas; (2) Effects on the lymphoid/hematopoietic system, such as decreases in 
reticulocytes, lymphocytes and bone marrow cells; (3) Effect on the pituitary gland, such as low 
pituitary weight and/or atrophy of the anterior lobe in the pituitary gland; (4) Effects on the 
epithelium, such as thinning of the epithelium in the tongue, esophagus or cornea; (5) Effects on the 
reproductive organs, such as atrophy; (6) Inhibitory effects on angiogenesis in the bone marrow, bone 
and ovaries. All the changes showed partial to complete recovery at the end of the 4-week Recovery 
Period. The no observed adverse effect level (NOAEL) was below 0.05 mg/kg/day and the MTD was 
6.25 mg/kg/day in the 4-week GLP study. 
In a GLP, 12-week, oral intermittent dose toxicity study (4 cycles; 2-weeks on followed by 1-week 
off/cycle, dose levels: 0, 0.05, 0.25, 1.25 and 6.25 mg/kg/day) in mature rats (14 weeks old at dose 
initiation), the key findings mainly reflected those described previously in the 4-week GLP study.  
The incidence/degree was lower compared with those observed in the 4-week GLP study. 
Additionally, there was an increase in incidence/degree of spontaneous inflammatory changes 
(mononuclear cell infiltration and inflammation, these changes were noted in the control group also) 
in the joint, lung, pancreas, harderian glands, tongue, large intestine and/or skin (mouth). The NOAEL 
was 0.05 mg/kg/day, and the MTD was 6.25 mg/kg/day in the 12-week intermittent dose GLP study.  
In a GLP 13-week oral repeat-dose toxicity study (dose levels: 0, 0.05, 0.25, and 1.25 mg/kg/day) in 
mature rats (14 weeks old at dose initiation) study, the toxicological profile was essentially similar to 
those of the 4-week and 12- week intermittent dose GLP studies in rats. The key findings mainly 
reflected those described as (1), (2), (3) and (6) in the 4-week GLP study. These adverse effects were 
partially or completely reversible at the end of the 4-week recovery period, and therefore these 
findings were considered to be non-severe. The NOAEL was 0.05 mg/kg/day, and the MTD was 1.25 
mg/kg/day in the 13- week GLP study. 
 
 

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Repeat-dose toxicity study in cynomolgus monkeys 
In a GLP, 4-week, oral repeat-dose toxicity study (dose levels: 0, 0.032, 0.16, 0.8 and 4/2 mg/kg/day) 
in mature cynomolgus monkeys (4 to 6 years old at dose initiation), 4 animals receiving 4 mg/kg/day 
(2 of each sex) were sacrificed in extremis (on Days 15, 18, 21 and 28 respectively). As a result, the 
highest dose of 4 mg/kg/day was reduced to 2 mg/kg/day from the 3rd week of the dosing period. The 
key findings observed in this study mainly reflected those described 4-week GLP rat study. Additional 
changes seen in cynomolgus monkeys were atrophy of the gastric gland. All the changes showed 
complete recovery at the end of the 4-week recovery period. The NOAEL was 0.16 mg/kg/day and 
the MTD was 0.8 mg/kg/day in the 4-week GLP study. 
In a GLP, 12-week, oral intermittent dose toxicity study (4 cycles; 2-weeks on followed by 1-week 
off/cycle, dose levels: 0, 0.12, 0.6 and 3/1.5 mg/kg/day) in mature cynomolgus monkeys (4 to 7 years 
old at dose initiation), marked body weight loss was observed in the highest dose group. As a result, 
the highest dose of 3 mg/kg/day was reduced to 1.5 mg/kg/day from the 3rd-cycle. The key findings 
observed in this study mainly reflected those described as (1), (2) and (5) in the 4-week GLP rat study. 
The incidence of these findings in the 12-week intermittent dose GLP study was lower compared with 
those observed in the 4-week GLP study. 
The NOAEL was 0.12 mg/kg/day and the MTD was 1.5 mg/kg/day in the 12-week intermittent dose 
GLP study. There was no evidence of genotoxic liability for MEN1611 in the Ames, chromosome 
aberration, or in vivo rat micronucleus tests.  
There were no effects on the central nervous and respiratory systems in safety pharmacology studies 
in rats up to 45 mg/kg, by the oral route. The cardiovascular safety pharmacology studies, including 
in vitro human Ether-à-go-go-related gene (hERG) assay and an in vivo telemetry study in 
cynomolgus monkeys, indicated no QT prolongation risk up to 10 μmol/L (the hERG assay) and up 
to 9 mg/kg (the initial monkey telemetry study by the oral route). However, transient hypertension 
(approximately 20 mmHg increase compared to the predose values) was observed at 0.5 mg/kg and 
above in the monkey telemetry study by the oral route. However, transient hypertension (approx. 
20 mmHg increase compared to the pre-dose values) was observed at 0.5 mg/Kg and above in the 
monkey telemetry study by the oral route. In a further telemetry study with 2-week repeat dose oral 
administration at 1.5 mg/kg/day, similar transient hypertension was observed, but, these findings did 
not worsen with repeated administration. In order to achieve high systemic exposure, a telemetry 
study in cynomolgus monkey was conducted using the intravenous (IV) route, and this confirmed 
similar transient hypertension at 1 and 3 mg/kg; however, this IV study confirmed that no QT 
prolongation up to 10 mg/kg. 
Potential effects of MEN1611 on reproductive and developmental toxicity have not been evaluated 
in a standard reproductive toxicity study. However, it is considered that the atrophic changes in the 

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reproductive organs in both species used in the repeat dose toxicity studies are indicative of possible 
effects on reproductive and developmental toxicity. 
As the observed adverse effects following repeated administration were completely or partially 
reversible, they were not considered to pose a significant risk to human patients receiving oral 
administration in a well-controlled and a well-monitored clinical setting. The effects of MEN1611 on 
pregnancy and embryo-fetal development in the rat following oral administration were investigated 
in a preliminary non-GLP study. Six females/group were dosed from Day 6 until Day 17 post-coitum 
at dose levels of 0.25, 1.25 and 6.25 mg/kg/day. The dose level of 6.25 mg/kg/day presented signs of 
maternal, fetal, and embryo-toxicity. Females treated at dose levels of 0.25 mg/kg/day and 1.25 
mg/kg/day did not show any change both during the pregnancy and at post mortem examination. No 
external alterations were observed also on fetuses. However, even if maternal toxicity has not been 
observed at these lower dose levels, a possible teratogenic effect cannot be excluded since no visceral 
and skeletal examinations of fetuses was performed. 
6.6.3 
Clinical Experience 
In the PA-001 EU dose-escalation first-in-human (FIH) study, conducted by Chugai Pharmaceutical, 
MEN1611 was administered to patients with advanced solid tumours for which there was no standard 
treatment available. The study was conducted in 4 clinical centres from August 2010 until 
December 2012.  
Of the 39 patients enrolled in PA-001 EU study, 38 patients were included in the safety population. 
MEN1611 was generally well tolerated and the majority of adverse events (AEs) and drug-related 
AEs were Grade 1 or 2 and 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 patients in the 48 mg twice daily (BID) cohort 
(aspartate aminotransferase [AST] increased), 2/3 patients in the 72 mg BID cohort (fatigue and 
encephalopathy) and 2/5 patients 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 patients, respectively.  
At single and repeated doses, MEN1611 was absorbed and eliminated rapidly, with a low contribution 
of renal excretion on its total elimination. MEN1611 exposure AUC and Cmax was subject to large 

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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 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 platelet-rich plasma (PRP), as a proof of 
mechanism for MEN1611, were observed for daily doses greater than 32 mg, after both single and 
repeat dose administration. The temporal relationship between reduction in phosphorylation of AKT 
and dosing administration suggested target engagement for less than 24 hours, indicating the need to 
increase dosing frequency to BID. Inhibition of p-AKT was also observed in 2 of the 3 tumour biopsy 
samples obtained in the study: Decreases of p-AKT from baseline was observed in one patient both 
in the 96 mg QD cohort (-81%) and in the 56 mg BID cohort (-48.5%) while one patient in the 56 mg 
QD cohort had an increased p-AKT compared to baseline (+37.0%). 
No patients had the best overall response of complete response (CR) or partial response (PR). Stable 
disease (SD) was reported in 8/33 (24.2%) patients in total. Although there were no patients who 
showed CR or PR, ≥ 30% decreases of standardised uptake value were reported in 4/23 patients in 
the 2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging after 1 week of treatment 
(Cycle 1, Day 8). One patient with mCRC treated at 96 mg dose, had a SD for more than 16 weeks. 
 
MEN1611-01 (B-PRECISE-01) is an open-label, multicenter, Phase Ib dose escalation study of 
MEN1611 combined with trastuzumab+/-fulvestrant, in patients with PIK3CA mutated HER2-
positive locally recurrent unresectable (advanced) or metastatic (a/m) breast cancer progressed to 
anti-HER2 based therapy. The study involves patients pre-treated with at least 2 lines of anti HER2 
based therapy. The study is aimed to determine the MTD and RP2D of MEN1611 (at three ascending 
doses 16mg, 32mg and 48mg) when administered in combination with trastuzumab+/-fulvestrant. 
After completing the dose escalation phase, the 48 mg BID dose had been selected as RP2D and 
subsequently, the cohort expansion phase has been opened in two groups of patients: 1) MEN1611 
plus trastuzumab and fulvestrant in HER2, hormone receptor positive postmenopausal women and 2) 
MEN1611 plus trastuzumab in HER2 positive patients, hormone receptor negative men and women 
and premenopausal women. 
The study recruitment started in July 2018 (first patient pre-screened) and was closed in December 
2021. A total of 62 patients have been treated in the study, 56 of them at the RP2D of 48 mg BID: 31 
in the triple and 25 in the double combo arms with MEN1611 being well tolerated. As of 15 May2023, 
three patients continue on treatment and are under follow up for safety and efficacy. 
 

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6.7 Risk Benefit Assessment 
Treatment options for patients with RAS WT, PI3K mutated mCRC after progression with standard 
chemo- and targeted therapy including anti-EGFR containing regimens remain poor. The 
PI3K/protein kinase B (AKT)/mTOR signalling pathway, which controls numerous cellular 
functions, is frequently deregulated in these tumours. 
Hyperactivation of the PI3K cascade is one of the principal mechanisms of resistance involved in the 
lack of response to anti-EGFR antibodies. 
Because PI3K is the most proximal component of the pathway, targeting PI3K itself rather than AKT 
or mTOR might induce a pronounced inhibition of the downstream components and reverse eventual 
resistance to previous treatments. A number of PI3K inhibitors are under clinical investigation in 
different type of tumours, including pan-PI3K inhibitors targeting all four isoforms of class I PI3K 
(e.g. buparlisib, pictilisib), as well as isoform-selective inhibitors, especially PI3Kα inhibitors, such 
as taselisib and alpelisib. Considering the high frequency of toxicity of pan-PI3K inhibitors, some of 
them have been discontinued despite the evidence of clinical activity, mostly in combination (i.e. 
buparlisib).  
MEN1611 is a potent, selective class I PI3K inhibitor with a strong inhibitory activity against PI3Kα 
which has shown cytotoxic activity in in vitro and in vivo models as single agent and in combination. 
Moreover, in the FIH study conducted by Chugai Pharmaceutical, MEN1611 has shown a good safety 
profile, in line with the class of agent, furthermore an encouraging anti-tumour activity, resulting in 
disease stabilization in 24% of treated patients, has been observed (PA-001 EU Clinical Study 
Report). Therefore, given the lack of standard therapeutic options for the selected patient population, 
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 cetuximab in 
patients with PIK3CA mutated, RAS WT mCRC progressed over at least two previous lines of 
irinotecan, oxaliplatin, 5-FU and anti-EGFR antibodies-containing regimens. If this study 
demonstrates an efficacy signal, MEN1611 could offer a new therapeutic approach in the treatment 
of this setting.  
In this study, MEN1611 treatment will be continued until objective disease progression is 
documented or another criterion for discontinuation (e.g. unacceptable toxicity, withdrawal of 
consent) is met, for patients affected by mCRC. To mitigate the risk of the administration of the study 
treatment and to guarantee the patients’ safety during the study participation, the following measures 
have been applied in accordance with European Medicines Agency (EMA) guidelines (37):  

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1) It was decided to consider a starting dose of 48 mg BID according to the data included in the 
Investigator’s Brochure (IB), it being the MTD in the FIH study. The 48 mg given BID offered 
a good safety profile, as MEN1611 was well tolerated and successfully inhibited the PI3K 
pathway.  
2) Although MEN1611 did not show to induce any mood disorder in the clinical studies up to 
date, patients having any serious and/or unstable pre-existing psychiatric or neurologic illness 
or other conditions that could interfere with patient's safety are to be excluded, considering 
the toxicity profile of the class of drug (i.e. buparlisib).  
3) MEN1611 as other PI3K inhibitors are reported to cause hyperglycaemia; for this reason, 
patients with uncontrolled diabetes mellitus (glycated haemoglobin [HbA1c] > 7%) and 
fasting plasma glucose (FPG) > 126 mg/dL will not be included in the study; a strict 
monitoring of safety laboratory tests including blood sugar levels as well as recording of any 
AEs will be done at each visit and appropriate therapy will be started immediately at 
occurrence. 
4) Pre-clinical study showed effects on the lymphoid/hematopoietic system, such as decreases 
in reticulocytes, lymphocytes and bone marrow cells; for this reason, a strict monitoring of 
safety laboratory test including haematology as well as recording of any AEs will be done at 
each visit and appropriate supportive care will be started immediately. In the B-PRECISE-01 
(as of 30 January 2023) at the 48 mg BID dose (n=58), 20 (35.71%) patients had TEAEs in 
the SOC Blood and Lymphatic System Disorders (regardless of causality): 19 (33.9%) 
anaemia, 18 (32.14%) leukopenia, 5 (8.93%) neutropenia, 5 (8.93%) thrombocytopenia, and 
2 (3.57%) lymphopenia. Out of them, 6 (10.71%) were of CTCAE (v4.03) ≥ grade 3 severity, 
4 (7.14%) anaemia, with neutropenia and thrombocytopenia occurring to one patient (1.79 %) 
each.  
5) Diarrhoea is a class toxicity of PI3K inhibitors (38). In the FIH Chugai Pharmaceutical study 
(PA-001EU), one of the most common side effects was gastrointestinal disorders. In the B-
PRECISE-01 (as of 30 January 2023) at the 48 mg BID dose, 37 (66.1%) patients had 
diarrhoea (regardless of causality), it was of CTCAE (v4.03) ≥ grade 3 severity in 6 (10.7%) 
patients. Furthermore, diarrhoea is associated with the use of cetuximab and itis a frequent 
symptom associated with tumour. We have clearly stated in the exclusion criteria that National 

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Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 
v5.0) Grade ≥ 2 diarrhoea, which is not resolved in the week prior to the start of treatment, 
will be considered an exclusion criterion. Physical examination and laboratory tests will be 
performed at each visit and appropriate supportive care will be started immediately at 
occurrence as per investigator judgement. 
6) Considering the toxicity profile of the class of PI3K inhibitors, preliminary data from B-
PRECISE-01 study (as of 30 January 2023) at the 48 mg BID dose, shows 32 (57.14%) 
patients had TEAEs in the SOC Skin and Subcutaneous Tissue Disorders (regardless of 
causality), it was of CTCAE (v4.03) ≥ grade 3 severity in 2 (3.6%) patients. Based on that, 
the combination of MEN1611 with cetuximab, cutaneous reaction is considered a potential 
risk for the patients.  
The most frequent cutaneous toxic effects reported in clinical studies with PI3K inhibitors 
have been maculopapular eruption, pruritus, and dry skin. In the B-PRECISE-01 study the 
most common TEAEs were rash in 15 (26.8%) and pruritus in 6 (10.71%) patients. For this 
reason a complete clinical examination including skin will be performed at screening and 
throughout the study at each study visit.  
In addition, due to the known cetuximab skin toxicity, patients will receive general 
educational and prophylactic measures (see Section 8.4.6). Consultation with a dermatologist 
shall be performed in case skin toxicity Grade ≥ 3 is assessed (the AE has to be followed until 
resolution to Grade 1). The frequency of dermatological visits can be increased upon 
Investigator’s judgement. 
7) As highlighted above, no AE due to drug phototoxicity was reported in the FIH study. In the 
B-PRECISE-01 study (as of 30 January 2023) at the 48 mg BID dose, 10 (17.9%) patients 
had TEAEs in the SOC Eye Disorders, all of them were CTCAE v4.03 grade 1 or 2 severity, 
the most common were: dry eye in 4 (7.1%%), blepharitis in 3 (5.4%) and vision blurred in 2 
(3.6%). Considering the eye toxicity associated with cetuximab, we want to exclude any 
potential risk for the patients under treatment with the combination. Patients will receive 
complete physical examination at each cycle including eyes. Ophthalmic visits shall be 
performed for any Grade ≥ 2 eye disorder and repeated bi-weekly until resolution to Grade 1 
(the frequency can be increased upon Investigator’s judgement). 

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8) Respiratory disorders including fatal cases have been reported in patients treated within the 
EGFR-pathway (both cetuximab and PI3K inhibitors) (38). Confounding or contributing 
factors, such as concomitant chemotherapy known to be associated with interstitial lung 
disease (ILD), and pre-existing pulmonary diseases were frequent in fatal cases. Patients with 
known active or uncontrolled pulmonary dysfunction are excluded from this study. Patients 
enrolled will be regularly questioned about pulmonary symptoms during the study. Should 
pulmonary symptoms appear during or after cetuximab treatment, a detailed description is 
required and investigators should use their discretion in ordering such diagnostic procedures 
as are necessary to elicit an accurate diagnosis. If pneumonitis/ILD is diagnosed, cetuximab 
and MEN1611 must be discontinued and the patient be treated appropriately. 
9) MEN1611 affected the blood pressure (BP), with transient hypertension (approx. 20 mmHg 
compared to the pre-dose values) in telemetered cynomolgus monkeys from 2 to 6 hours after 
dosing at 0.5, 1.5, 3.7 and 9 mg/kg, but with no effects on other parameters of the 
cardiovascular system. In the B-PRECISE-01 study, (as of 30 January 2023) at the 48 mg BID 
dose, 5 (8.9%) patients had hypertension (regardless of causality), most of them were CTCAE 
v4.03 grade 1 or 2 severity, and 1 of them of grade 3. A strict monitoring of safety includes 
vital sign and BP measurement. Therefore, to prevent such potential risks, patients with 
uncontrolled hypertension (defined as persistent BP of ≥ 150/90 mmHg despite treatment, 
measured on at least 2 separate occasions) will be not included in the study.  
10) As far as treatment with cetuximab is concerned, in order to mitigate the potential risk of 
severe and infusion reactions, for the first administration, patients will be monitored during 
cetuximab infusion and for at least 1 hour after end of the infusion. In order to mitigate the 
potential risk of severe and fast progressing infusion reactions, premedication including a 
corticosteroid and a histamine-1 (H1) receptor antagonist (e.g. d-chlorpheniramine or 
diphenhydramine) is recommended. Availability of resuscitation equipment must be ensured. 
In addition, patients will be informed about the possibility of such a late onset and instructed 
to contact the physician if symptoms or signs of an infusion-related reaction occur (see Section 
8.4.5). 
11) The potential for DDI between MEN1611 and cetuximab is relatively low; indeed, 
considering the pathways involved in the elimination of a small molecule (e.g. renal and 

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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 cetuximab. Nevertheless, 
MEN1611 PK will be characterized in combination with cetuximab and compared with 
MEN1611 PK as single agent, to assess any potential interaction. 
 
 
 
 
 
 
 
 
  
6.7.1 
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 patients, site staff and 
the society as a whole. 
This is a phase Ib/II clinical trial for heavily pre-treated patients with metastatic colorectal cancer 
with few tolerable and efficacious therapeutic available options as per standard of care. The eligibility 
of patients to the study will be evaluated by the treating physician/PI/sub-investigator 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 patients and care 
providers. 
Measures to mitigate the additional risks caused by COVID-19 are: 

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 Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered. 
 Patients 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. 
 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 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 Cetuximab administration 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  
7.1 Primary Objectives 
Step 1: 
 To determine the RP2D of MEN1611 when administered orally in combination with 
cetuximab to patients with PIK3CA mCRC failing irinotecan, oxaliplatin, 5-FU, and anti-
EGFR containing regimens. 
Step 2:  
 To assess the anti-tumour activity of MEN1611 in combination with cetuximab in patients 
with PIK3CA mutated mCRC failing irinotecan, oxaliplatin, 5-FU, and anti-EGFR containing 
regimens. 
7.2 Secondary Objectives 
 To assess the safety and tolerability of MEN1611 in combination with cetuximab. 
 To assess the PK profile of MEN1611 when given in combination with cetuximab. 
7.3 Exploratory Objectives 

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8 INVESTIGATIONAL PLAN 
8.1 Overall Study Design and Plan Description 
This is an open-label, dose-confirmation and cohort expansion, multicentre, Phase Ib/II study to be 
conducted in approximately 29 sites in Europe and US. 
The study will consist of 2 sequential steps: 
Step 1 (Confirmation of Dose for Cohort Expansion):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Step 2 (Cohort Expansion Phase): 
 
 
   
 
 
 
 
 
 
 
 

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8.2 Selection of Study Population 
Patients meeting all the following criteria will be eligible for entry into the pre-screening: 
1. Able to give written informed consent. 
2. mCRC. 
3. Progression or recurrence following prior anti-EGFR containing regimen and at least in 
second line of treatment for mCRC. 
4. Known N-K-RAS (exons 2, 3 and 4) WT status. 
5. Known BRAF WT or unknown BRAF status.  
6. Male and female aged ≥ 18 years. 
 
Patients will not be eligible for entry into the pre-screening if they meet ANY of the following 
exclusion criteria: 
1. Patients with a known PIK3CA WT status 
Note: this exclusion criterion does not apply if PIK3CA WT status was assessed before the 
last anti-EGFR containing regimen. 
2. Previous treatment with PI3K inhibitor. 
3. Hypersensitivity and/or contraindication to MEN1611, cetuximab or to any component of 
the formulations. 
4. Inability or unwillingness to abide by the study protocol; legal incapacity or limited legal 
capacity. 
 
At the Pre-screening Visit, all patients will sign the ICF to perform mutational analysis for PIK3CA, 
BRAF and N-K-RAS in plasma (ctDNA centrally analysed). Inclusion into the study will be done 
based on the results of the ctDNA. 
 
Eligibility of patients to the study will be checked at Screening Visit and re-checked prior to the 
start of any treatment. 
Patients will be included only if they meet all of the patient inclusion criteria (Section 8.2.1) and none 
of the exclusion criteria (Section 8.2.2), providing written informed consent. 
8.2.1 
Inclusion Criteria 
Patients meeting all the following criteria at Screening Visit will be eligible for entry into the study: 
1. Able to give written informed consent before any study related procedure. 

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2. Histological documentation of adenocarcinoma of the colon or rectum with radiological 
evidence of progressive disease after last treatment received. 
3. Progression or recurrence following irinotecan, oxaliplatin, fluoropyrimidine containing 
regimen and anti-EGFR containing regimens for metastatic disease. Patients who have a 
history of intolerance of irinotecan-based therapy or who are ineligible to receive irinotecan 
are also eligible as long as they have received a prior oxaliplatin-based therapy. Patients who 
have a history of intolerance of oxaliplatin-based therapy or who are ineligible to receive 
oxaliplatin are also eligible as long as they have received a prior irinotecan-based therapy. 
4. Best response according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria 
to the last anti-EGFR containing regimen of PR or SD for at least 4 months. 
5. Measurable disease according to RECIST criteria, version 1.1. 
6. Having a tumour N-K-RAS (exons 2, 3 and 4) and BRAF WT harbouring a PIK3CA mutation, 
as per centrally-analysed ctDNA during the [pre]-screening period using a validated test. 
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 
8. Life expectancy ≥ 12 weeks.  
9. Adequate cardiac function as defined by left ventricular ejection fraction of ≥ 50% measured 
by a multigated acquisition (MUGA) scan or echocardiography (ECHO). 
10. Adequate bone marrow function as defined by absolute neutrophil count (ANC) of 
≥ 1.5x 109/L, platelet count of ≥ 100.0x 109/L and haemoglobin of ≥ 9 g/dL. 
11. Adequate liver function, as determined by total bilirubin within upper limit of normal (ULN) 
(≤ 1.5x ULN if documented liver involvement; ≤ 3x ULN with direct bilirubin ≤ 1.5x ULN 
in case of patients with coexisting known Gilbert’s disease) and/or AST and alanine 
aminotransferase (ALT) ≤ 2.5x ULN (≤ 5x ULN if liver metastases). 
12. Adequate renal function assessed by creatinine clearance ≥50 mL/min (calculated by 
Cockcroft-Gault formula). 
13. Adequate electrolytes (serum potassium and magnesium levels within institutional normal 
limits). Replacement treatment to achieve adequate electrolytes levels is allowed. 
14. Not pregnant, not breastfeeding, and at least 1 of the following conditions applies: 
a) Not a woman of childbearing potential (WOCBP) (see Appendix I, Section 13.1). 
OR 
b) A WOCBP who agrees to use highly effective contraception 4 weeks before the first dose 
of the study treatment, during the treatment period and for 6 months following the last dose 
of the study treatment. Patients should not breastfeed during and at least for 6 months after 
the last dose of the study treatment. 

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15. Male patient who is surgically sterile or male patient who is willing to agree and have his 
female partners (if WOCBP) agreeing with the true abstinence (refrain from heterosexual 
intercourse) or who agrees to use and to have his female partners (if WOCBP) using barrier 
contraceptive measures during the entire study treatment period and for 6 months after the last 
administration of study treatment, and agrees to refrain from donating sperm during the entire 
study treatment period and for 6 months after the last administration of study treatment. 
Note: Inclusion criteria 7 and 10 to 13 (if applicable) will be re-evaluated prior to the start of any 
study treatment (Day 1 of Cycle 1). 
8.2.2 
Exclusion Criteria 
None of the following exclusion criteria shall be met at Screening Visit and will be re-checked at 
Day 1 Cycle 1: 
1. Previous treatment with a PI3K inhibitor. 
2. Hypersensitivity and/or contraindication to MEN1611, cetuximab or to any component of the 
formulations. 
3. Inability to swallow oral medications. 
4. Brain metastases, with the exception of patients with previously treated brain metastases 
(including radiation and/or surgery) > 4 weeks before the Screening Visit and only if 
clinically stable (as determined by the Investigator), and not receiving corticosteroids. 
5. NCI CTCAE v5.0 Grade ≥ 2 diarrhoea, which is not resolved in the week prior to the start of 
the study treatment (Day 1 of Cycle 1). 
6. History of significant, uncontrolled or active cardiovascular disease, specifically including, 
but not restricted to: 
a) Myocardial infarction within 6 months prior to the first dose of any study treatment (Day 
1 of Cycle 1,). 
b) Acute coronary syndromes (including unstable angina, coronary artery bypass grafting 
[CABG], coronary angioplasty or stenting) within 6 months prior to first dose of any 
study treatment (Day 1 of Cycle 1,). 
c) Congestive heart failure (CHF) New York Heart Association Class III-IV. 
d) Clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), 
as determined by the Investigator. 
e) Long QT syndrome or other risk factors for “Torsades de Pointes” or increased QTc 
interval according to Fridericia formula (QTcF > 450 msec for males and 
QTcF > 460 msec for females). 

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f) Ventricular arrhythmia.  
7. Symptomatic thromboembolic events or cerebrovascular accident including transient 
ischaemic attack within 6 months prior to the start of any study treatment (Day 1 of Cycle 1). 
8. Uncontrolled hypertension (defined as persistent BP of ≥ 150/90 mmHg despite treatment, 
measured on at least 2 separate occasions). 
9. Known active or uncontrolled pulmonary dysfunction. 
10. Any serious and/or unstable pre-existing psychiatric or neurologic illness or other conditions 
that could interfere with patient’s safety. 
11. Uncontrolled diabetes mellitus (HbA1c > 7%) and FPG > 126 mg/dL. 
12. Known history of human immunodeficiency virus (HIV) infection or active infection with 
hepatitis C virus (HCV) or hepatitis B virus (HBV).  
13. Patients diagnosed with another primary malignancy, except for: adequately treated non-
melanoma skin cancer or cervical cancer in situ; or patients with another primary malignancy 
who are definitively relapse-free for at least 3 years since the diagnosis of the other primary 
malignancy. 
14. Concurrent chronic immunosuppressive treatment either with steroids or other 
immunosuppressive agents. 
15. Any chemotherapy, radiotherapy, immunotherapy, major surgery, biologic therapy or any 
other investigational agent within 28 days of the first administration of the study treatment 
or within five times the half-life of the investigational agent, whichever is longer. 
Note: Patients may receive palliative radiotherapy for painful bone metastases, as long as 
≤ 25% of the bone marrow was irradiated and does not affect target and non-target lesions 
being assessed. (Please see section 8.4.8.) 
16. 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. 
17. 
 
 
 
 
18. Pregnant or breastfeeding women. 
19. Inability or unwillingness to abide by the study protocol; legal incapacity or limited legal 
capacity. 
20. Warfarin sodium therapy or any other coumadin-derivative anticoagulant. 

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8.2.3 
Withdrawal of Patients from the Study or Discontinuation of the Study 
Treatment  
Participation in the study is strictly voluntary and patients have the right to withdraw from the study 
at any time without explanation. This will not affect their rights for future medical care. Patients 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 patient withdrawal are listed below: 
 Informed consent withdrawn or the patient requests discontinuation from the study. 
 Any medical condition or personal circumstance which, in the opinion of the Investigator or 
the Sponsor, exposes the patient to risk by continuing in the study or does not allow the patient 
to adhere to the requirements of the protocol. 
 Death. 
8.2.3.2 
Withdrawal from the Study Treatment 
Patients will be withdrawn from the study treatment if they experience: 
 Any protocol deviation which in the opinion of the Investigator or the Sponsor exposes the 
patient to risk by continuing the treatment. 
 Any medical condition or personal circumstance or AE with a possible, probable or certain 
drug-causality as per Investigator’s judgement which exposes the patient to risk by continuing 
the treatment. 
 Disease progression. 
 Delay in scheduled treatment exceeding 21 days due to study drug related toxicity. 
 Occurrence of pregnancy. 
 Patient’s request. 
All patients 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 patient’s 
withdrawal can replace the End of Study Visit provided that all assessments/procedures scheduled 
for this visit are completed.  
If a patient prematurely terminates the study as per patient’s request, data already collected will be 
used and analysed for the purpose of the study, as per local regulation. 

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In case of withdrawal of consent, the patient may choose if samples/images which are already 
collected but not analysed yet, can be analysed or shall be destroyed. 
During the Dose-confirmation Phase, patients not evaluable for DLT will be replaced. 
8.2.4 
End of Study 
After the End of Study Visit, all patients evaluable for efficacy will be followed for survival status 
according to local practice (a visit or a telephone call) every 12 weeks up to the end of study. 
The study ends with the End of Study Visit of the last patient 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 the End of Study must be recorded and notified to the Sponsor. 
All biological samples except for safety blood samples collected along the study will be stored for a 
maximum of 10 years from the date of the Last Patient Last Visit. After 10 years, the samples will be 
destroyed. 
8.3 Identity of the Investigational Products 
8.3.1 
Description of the Investigational Medicinal Products 
MEN1611: 
The drug product MEN1611 is a hypromellose 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.  
 
Cetuximab: 
Authorized market preparations will be used as combination medication. The market preparation is a 
solution for infusion. Dilution of the market preparation should follow the instructions reported in the 
respective summary of product characteristics (SmPC). 
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 
(A.MRBS). 
MEN1611 16 mg capsules will be packaged as described below: 

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 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 wallets). The 
Al/Al blisters will be permanently fixed in blister wallets. 
Labelling: The IMP MEN1611 will be labelled in compliance with the current valid international and 
corresponding national requirements. The label will report 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 patient to keep MEN1611 
boxes according to the storage conditions given on the label. 
Distribution of MEN1611 treatment boxes to the study sites will be under responsibility of A.MRBS. 
Cetuximab: 
Cetuximab will be provided using authorized market preparations for EU and US sites. 
EU Sites: 
The primary packaging of the authorized market preparation will not be modified. Each vial will be 
labelled individually. The secondary packaging and labelling of cetuximab for EU sites is performed 
under the responsibility of the Department of Pharmaceutical Development of A.MRBS. As 
secondary packaging, the vials will be provided in labelled boxes. All labels will be in compliance 
with the valid international and corresponding national requirements. The labels will report 
instructions on how to administer and store cetuximab. 
Storage: At the study site, cetuximab must be kept in a secure area inaccessible to unauthorised 
individuals in accordance to the storage conditions given on the label. Distribution of cetuximab to 
EU study sites will be under responsibility of A.MRBS. 
US Sites: 
Cetuximab for US study sites will be provided by the respective site’s pharmacy. 
8.3.3 
Drug Accountability  
MEN1611 (EU and US) and Cetuximab (EU) 
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 patients, the inventory 
at the sites, including dates, quantities, expire dates and batch/serial number.  

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The Investigator will be responsible for documenting the dispensing of the study treatment to the 
patient by entering the unique medication 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 patient. The peel-off labels will be pasted onto these paper drug 
accountability forms.  
Patients will be instructed to return used or unused MEN1611 boxes at each visit to allow drug 
accountability for dispensed MEN1611. 
Cetuximab (for US sites only) 
The Investigator will be responsible for documenting the dispensing of the study treatment to the 
patient 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 patient. 
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. 
MEN1611 (EU and US) 
No later than the Site Close-out Visit, the used and unused MEN1611 IMP boxes shall be returned to 
the Department of Pharmaceutical Development of A.MRBS for destruction, 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. 
Cetuximab (for EU sites only) 
Used and unused cetuximab boxes shall be destroyed locally. Any local destruction of cetuximab 
requires a certificate of destruction, indicating the batch number and the box number. 
Cetuximab (for US sites only) 
Used cetuximab boxes shall be destroyed locally. 
8.4 Treatments 
8.4.1 
MEN1611 
Step 1 (Dose-confirmation Phase): MEN1611 as oral capsules of 16 mg strength will be orally 
administered BID (approximately 12 hours apart) for a continuous 28-days cycle. The starting dose 
of MEN1611 will be 48 mg BID for a total daily dose of 96 mg. In case 48 mg BID in combination 

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with cetuximab will represent the toxic dose level for this combination, a lower dose level of 32 mg 
BID will be tested in cohort 2. 
In this Phase, MEN1611 will be administered as below: 
 Cohort 1: MEN1611 48 mg (3 × 16 mg) capsules BID over 28-days’ cycle. 
 Cohort 2: MEN1611 32 mg (2 × 16 mg) capsules BID over 28-days’ cycle. 
 
Step 2 (Cohort-expansion Phase): MEN1611 as oral capsules will be orally administered BID for a 
continuous 28-days’ cycle at the RP2D as established in Step 1. 
MEN1611 capsules should be taken with a glass of water in fasting condition, i.e. at least 2 hours 
after a meal and at least 1 hour before the next meal. Patient should take capsules at approximately 
the same time each day. At Visit 2, Visit 3 and Visit 4 of Cycle 1, and at each following visits, 
MEN1611 will be administered at site using the new boxes dispensed at each visit.  
8.4.2 
Cetuximab 
In both Step 1 and Step 2, cetuximab will be administered IV weekly on Day 1, 8, 15 and 22 of every 
28-day cycle according to institutional standards.  
The initial cetuximab dose is 400 mg/m2 administered as a 120 minutes infusion on Day 1 of Cycle 1, 
followed by a weekly 250 mg/m2 dose administered as a 60-minute IV infusion. Premedication with 
a H1 receptor antagonist (e.g. d-chlorpheniramine or diphenhydramine) and a corticosteroid is 
required prior to cetuximab administration (see Section 8.4.8). Management of infusion reactions due 
to cetuximab are to be managed according to Section 8.4.5. 
MEN1611 will be given in combination with weekly IV infusion of cetuximab until objective disease 
progression is documented or another criterion for discontinuation is met. If cetuximab needs to be 
discontinued due to toxicity, continuation with MEN1611 as monotherapy should be considered and 
discussed with the Sponsor. 
8.4.3 
Treatment Compliance 
Patients will be asked to complete a paper patient diary for the duration of their treatment with 
MEN1611 to record the study treatment compliance (see Section 10.1.3). 
 

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8.4.4 
Management of Toxicities due to MEN1611 and Dosage Modification 

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8.4.5 
Management of Infusion-Related Reactions due to Cetuximab 
One of the main undesirable effects of cetuximab are infusion-related reactions, which occur with 
mild to moderate symptoms in more than 10% of patients and with severe symptoms in more than 
1% of patients. 
Prophylaxis of Infusion-Related Reactions: 
At least 1 hour prior to the first infusion of cetuximab, the patient must receive a premedication 
consisting of a corticosteroid and a H1 receptor antagonist.  
This premedication is strongly recommended prior to all subsequent infusions. 
As dexamethasone and prednisone are known to be inducers of isozyme CYP3A4, its administration 
during the study is allowed only prior to cetuximab infusions. In case the patient was receiving 
dexamethasone/prednisone before the study, the treatment should be stopped within a period 
corresponding to five times the half-life of the drug prior to the first MEN1611 administration (see 
Section 8.4.8). 
Cetuximab must be administered under the supervision of a physician experienced in the use of 
antineoplastic medicinal products. The infusion rate should be consistent with the local label but 
should not exceed 10 mg/min. Close monitoring is required during the infusion and for at least one 
hour after end of the infusion. If an infusion reaction occurs while cetuximab is being administered, 
the infusion should be stopped immediately, and the patients should be closely monitored and treated 
in line with institutional standards. Availability of resuscitation equipment must be ensured. 
Symptoms may occur during the first infusion and for up to several hours afterwards or with 
subsequent infusions. It is recommended to inform patients of the possibility of such a late onset and 
inform them to contact the investigator if symptoms or signs of an infusion-related reaction occur. 
Occurrence of a severe infusion-related reaction requires immediate and permanent discontinuation 
of cetuximab therapy and may necessitate emergency treatment. 
If during the first infusion, an infusion-related reaction occurs within the first 15 minutes, the infusion 
should be stopped. If an infusion-related reaction develops later during the infusion or at a subsequent 
infusion further management will depend on its severity: 
 
 

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Table 8-5  Management of Infusion-Related Reactions due to Cetuximab 
CTCAE v5.0 
Action 
Grade 1:  
Mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated. 
Decrease cetuximab infusion rate by 50% and 
monitor closely for any worsening. All subsequent 
infusions must also be administered at the reduced 
rate. 
Grade 2: 
Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (e.g. antihistamines, non-steroidal 
anti-inflammatory drugs [NSAIDs], 
narcotics, IV fluids); prophylactic 
medications indicated for <=24 hrs. 
Stop cetuximab infusion. Administer symptomatic 
treatment as medically indicated. Restart and 
complete the infusion at the discretion of the 
investigator. The infusion must be resumed at 
reduced rate (once resolved or decreased to Grade 1). 
Additional premedications such as antihistamines or 
low-dose systemic corticosteroids may be 
administered when the infusion is restarted and 
monitored closely for any worsening. All subsequent 
infusions must also be administered at the reduced 
rate. 
Grade 3:  
Prolonged (e.g. not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalisation indicated for clinical 
sequelae. 
Grade 4:  
Life-threatening consequences; urgent 
intervention indicated. 
Stop infusion immediately, treat symptoms 
vigorously (e.g. administer epinephrine, 
bronchodilators, antihistamines, glucocorticoids, 
intravenous fluids, vasopressor agents, oxygen etc., 
as medical indicated). Permanently discontinue 
cetuximab. 
Once a cetuximab infusion rate has been decreased due to an infusion reaction, it will be administered 
at the reduced rate for all subsequent infusions. Any rechallenge with cetuximab following an infusion 
reaction should be discussed with the Sponsor. 
 
 

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8.4.6 
Management of Skin Toxicities due to Cetuximab 
The main undesirable effects of cetuximab are skin reactions, which occur in more than 80% of patients. Clinical judgement and experience of the 
investigator should guide the management plan of each patient.  
General educational and prophylactic measures: Washing with lukewarm water, use shower oil or soap with neutral pH, use only perfume free cream, 
sunlight protection factor (SPF)≥25, wearing sun-protective clothes, application of topical agents (e. g. sunscreen, vitK1, emollient creams, topical 
steroids) in some areas such as face, scalp, neck, upper chest and upper back. Prophylactic recommendations should follow the clinical practice and 
local regulations for cetuximab administration. 
In symptomatic patients who develop skin toxicity it is recommended to receive antihistamine for pruritic lesions, silver nitrate or zinc oxide cream 
for fissuring and emollients for desquamation. 
 
Table 8-6  Management of Skin Rash (39)  
Severity/Grade 
of Skin Rash 
CTCAE v5.0 
Symptoms 
Cetuximab Dose Modifications 
Topical Treatment 
Systemic Treatment 
Intervention 
Grade 1 
(mild) 
Papules and/or pustules covering 
<10% of BSA, which may or may not 
be associated with symptoms of 
pruritus or tenderness 
No 
-Topical antibiotics, 
BID (e.g. 
Metronidazole cream) 
and/or 
-Topical 
corticosteroid 
-Vitamin K1 cream 
Possibly oral antibiotics 
(Doxycycline, 
Minocycline) 
General 
educational and 
prophylactic 
measures 
Grade 2 
(moderate) 
Papules and/or pustules covering 10 - 
30% BSA, which may or may not be 
associated with symptoms of pruritus 
or tenderness; associated with 
No 
Topical 
corticosteroids, (e.g. 
mometasone ) 
Oral antibiotics 
(Doxycycline 100 mg 
BID, Minocycline 50 TO 
100 BID)  
General 
educational and 
prophylactic 
measures 

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Severity/Grade 
of Skin Rash 
CTCAE v5.0 
Symptoms 
Cetuximab Dose Modifications 
Topical Treatment 
Systemic Treatment 
Intervention 
psychosocial impact; limiting 
instrumental ADL 
Topical antibiotics 
(clindamycin) 
 
Grade 3 
(severe) 
Papules and/or pustules covering 
>30% BSA with moderate or severe 
symptoms; limiting self-care ADL; 
associated with local superinfection 
with oral antibiotics indicated. 
 
Omit dose until resolved to ≤ G2. 
First occurrence: If there is an 
improvement continue at 100% 
dose.  
Second and third occurrences of 
severe skin reactions, cetuximab 
therapy must again be 
interrupted. Treatment may only 
be resumed at a lower dose level 
(200 mg/m² after the second 
occurrence and 150 mg/m² after 
the third occurrence), if the 
reaction has resolved to Grade 2. 
Fourth occurrence or not 
resolved to Grade 2 during 
interruption of treatment, 
permanent discontinuation of 
cetuximab treatment is required. 
 
 
 
 
 
Oral antibiotics 
(minocycline, 
doxycicline). 
Systemic Corticosteroids 
PO (methylprednisolone, 
prednisone)* according to 
investigator judgement.  
In highly 
symptomatic/non 
responsive patients: 
Isotretionin 0.3-05 
mg/Kg PO; 
Antihistamines im/iv 
(clorfenamine); 
Antibiotics 
(amoxicillin/ac. Clav). 
In addition to the 
interventions 
recommended for 
Grade 2 rash 
 
 
Consultation of 
dermatologist. 

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Severity/Grade 
of Skin Rash 
CTCAE v5.0 
Symptoms 
Cetuximab Dose Modifications 
Topical Treatment 
Systemic Treatment 
Intervention 
Grade 4 
(potentially 
life-
threatening) 
Life-threatening consequences; 
Papules and/or pustules covering any 
% BSA, which may or may not be 
associated with symptoms of pruritus 
or tenderness and are associated with 
extensive superinfection with IV 
antibiotics indicated; life-threatening 
consequences. 
 
Stop infusion immediately, 
contraindicate further use of 
cetuximab. 
 
 
Isotretionin 
(Corticosteroids IV 
(methylprednisolone, 
dexamethasone)* 
Antihistamines IV 
(clorfenamine) 
Antibiotics IV 
(amoxicillin/ac. Clav) 
Hospitalisation. 
Consultation of 
dermatologist. 

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If a patient experiences Grade 3 skin toxicity, cetuximab therapy may be deferred, without changing 
the dose level. If the toxicity resolves to Grade 2 or less by the following treatment period, the 
treatment may resume. With the second or third recurrences of Grade 3 skin toxicity, cetuximab 
therapy may again be deferred with concomitant dose reduction to 200 mg/m2 and 150 mg/m2, 
respectively. Cetuximab dose reductions are permanent. Patients should discontinue cetuximab if not 
resolved to Grade 2 or a fourth occurrence of Grade 3 skin toxicity occurs despite an appropriate dose 
reduction. 
8.4.7 
Management of Other Cetuximab-Related Adverse Events 
Diarrhoea 
Patients and patient’s caregivers should be carefully informed of possible severe toxic effects such as 
diarrhoea and abdominal cramps. Each patient should be instructed to have loperamide readily 
available and to begin treatment at the first episode of poorly formed or loose stools or the earliest 
onset of bowel movements more frequent than normally expected. The patient should be also 
instructed to notify the Investigator if diarrhoea or abdominal cramps occur. Patients should be 
supported as clinically indicated and treated for diarrhoea as per institutional guidelines, and/or as 
indicated in the locally approved prescribing information. 
Interstitial Lung Disease (ILD) 
Respiratory disorders, cases of ILD, including fatal cases, have been reported in patients treated with 
the EGFR-pathway. Confounding or contributing factors, such as concomitant chemotherapy known 
to be associated with ILD, and pre-existing pulmonary diseases were frequent in fatal cases. Patients 
with known active or uncontrolled pulmonary dysfunction are excluded from the study. Patients will 
be regularly questioned about pulmonary symptoms during the study. Should pulmonary symptoms 
appear during or after cetuximab treatment, a detailed description is required and investigators should 
use their discretion in ordering such diagnostic procedures as are necessary to elicit an accurate 
diagnosis. If ILD/ pneumonitis is diagnosed, cetuximab and MEN1611 must be discontinued and the 
patient be treated appropriately. 
Electrolyte Disturbances 
Progressively decreasing serum magnesium levels occur frequently and may lead to severe 
hypomagnesaemia in some patients. Hypomagnesaemia is reversible following discontinuation of 
cetuximab. If hypomagnesaemia is present, replacement should be managed with either oral or 
parental replacement or both, according to institutional practice. It is recommended that patient’s 
serum magnesium level should be maintained within the normal range during study treatment.  

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In addition, a patient’s serum potassium and calcium (adjusted for albumin) parameters are 
recommended to be maintained as per local medical practice. 
Eye disorders 
Cetuximab should be used with caution in patients with a history of keratitis, ulcerative keratitis or 
severe dry eye. Being a risk factor for keratitis and ulceration, the use of contact lens should be 
avoided. Patients presenting with signs and symptoms suggestive of keratitis such as acute or 
worsening: Eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye 
should be referred promptly to an ophthalmology specialist. Any ocular disorder Grade ≥2 will be 
referred to an ophthalmology specialist until resolution to Grade 1 (or even more frequently, if 
indicated). If a diagnosis of ulcerative keratitis is confirmed, treatment with cetuximab should be 
interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment 
should be considered according investigator and sponsor judgement.  
All other cetuximab-related AEs will be managed according to information provided in the SmPC 
and local hospital guidelines. 
8.4.8 
Prohibited and Concomitant Medications 
During the study patients are not allowed to receive any chronic treatment with steroids or another 
immunosuppressive agent. Premedication using a corticosteroid and a H1 receptor antagonist 
(including but not limited to d-chlorpheniramine or diphenhydramine) is allowed. Corticosteroids can 
be used only as premedication. 
Any chemotherapy, radiotherapy, immunotherapy, biologic treatment, and endocrine therapy are not 
allowed during the study and within 28 days or within five times the half-life of the investigational 
agent, whichever is longer of the first administration of any study treatment (Day 1 of Cycle 1). 
Patients may receive palliative radiotherapy for painful bone metastases, as long as ≤ 25% of the bone 
marrow was irradiated and does not affect target and non-target lesions being assessed. Patients may 
also receive bisphosphonates for the treatment of bone metastases.
 
 
 
 
  
Within 28 days or within five times the half-life of the investigational agent, whichever is longer prior 
to Screening Visit no other investigational agent is allowed to be taken. 
Concomitant and prior (i.e. within 28 days before Screening) medications shall be carefully checked 
since the use of the above reported medications may represent an exclusion criterion making the patient 

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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. 
8.4.9 
Dietary and Lifestyle Restrictions 
No food and drink containing grapefruit and quinine-containing products (e.g. tonic water) may be 
consumed from at least 2 weeks before the first administration of MEN1611, throughout the study and 
until the End of Study Visit.  
Alcohol consumption must be avoided from 48 hours before and during any study visit. Patients 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). 
8.5 Study Procedures and Assessments 
8.5.1 
Study Procedures 
The study procedures are depicted in the study flow chart (see Section 2.2) and summarised below by 
Pre-screening Period, Screening Period, and 28-day treatment cycles, each requiring 4-weekly study 
visits until the End of Study Visit. After the End of Study Visit, all patients evaluable for efficacy will 
be followed for survival status according to local practice (a visit or a telephone call) every 12 weeks up 
to the end of study. 
Pre-screening Period: 
At the Pre-screening Visit, all pre-screening eligible patients will perform mutational analysis for 
PIK3CA, BRAF and N-K-RAS in plasma (ctDNA centrally analysed) following provision of the 
written pre-screening informed consent. Inclusion into the study will be done based on the results of 
the ctDNA.  
Screening Period (Day -28 to Day -1): 
During the 28 days prior to the first dose of MEN1611 and following provision of written informed 
consent, each patient will be screened for eligibility. 
Patients entering the screening period with pre-screening ctDNA test older than 3 months need 
to be centrally re-tested for PIK3CA, N-K-RAS and BRAF in plasma. 
 
The following procedures will be performed at Screening: 
 Check of inclusion/exclusion criteria. 
 Recording of demographic data. 
 Standard medical, surgical and medication history. 

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 Assessment of ECOG PS. 
 Smoking history and current smoking status. 
 Physical examination including vital signs (i.e. BP, heart rate, respiratory rate, body 
temperature) and weight. 
 Recording of AEs and concomitant medications. 
 12-lead ECG record. 
 Tumour assessment using RECIST v1.1 for patients with measurable disease not older than 
2 weeks as assessed by:  
- Computed tomography (CT) scan with IV contrast medium of chest, abdomen and pelvis as 
preferred technique. If contraindications to contrast medium are present, a CT scan without 
contrast medium of chest and magnetic resonance imaging (MRI) of abdomen and pelvis 
could be used.  
- MRI or CT scan of the brain in patients with a history of asymptomatic brain metastases. 
Whole body bone scan, if clinically indicated. 
 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, hepatitis B surface antigen (HBsAg), HBV-DNA, 
HCV-ribonucleic acid (HCV-RNA). 
Note: In case the laboratory tests for anti-HIV antibodies, anti-HBcAg antibodies, anti-
HBsAg antibodies, HBsAg, HBV-DNA and HCV-RNA have been performed within 
3 months prior to Screening Period in the context of the standard patient’s management; these 
tests will not be repeated. 
 Blood samples for ctDNA ONLY if pre-screening ctDNA test is older than 3 months. 
 Serum pregnancy test (if applicable). 
 Sample for urinalysis. 
A screen failure is defined as follows: 
 A patient who does not meet the eligibility criteria required for study participation during the 
Screening Period. 
 A patient who no longer meets eligibility criteria at study Visit 1 (i.e. Day 1 of Cycle 1, when 
applicable). 
 A patient whose time window between Screening and Visit 1 (i.e. Day 1 of Cycle 1, when 
applicable) is longer than 4 weeks. 
Note-1: Study procedures under Screening Visit may occur also on more than one day. 

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Note-2: Results of safety laboratory tests (chemistry, haematology, coagulation, urinalysis and 
pregnancy test, when appropriate), and ECG, which have been performed in the context of the 
standard patient’s management, can be recorded in the eCRF under Screening Visit procedures, 
provided that they have been done the day before start of Screening Period. 
Note-3: If the complete assessment of the eligibility criteria is available within 3 days from the end 
of the Screening Period, the patient’s participation in the trial can be discussed with the Sponsor 
Medical Monitor. 
Screen failures can be re-screened upon Sponsor Medical Monitor’s approval. 
 
Cycle 1: 
Visit 1 – start of MEN1611 treatment (Day 1): 
(All assessments can be performed within 48 hours prior to administration of the study treatment at 
site, unless otherwise indicated.) 
 Re-evaluation of inclusion/exclusion criteria and confirmation of patient’s eligibility prior to 
the start of the study treatment. 
 Tumour assessment using RECIST v1.1 for patients with measurable disease performed 
within the last 4 weeks as assessed by: 
- CT scan with IV contrast medium of chest, abdomen and pelvis as preferred technique. If 
contraindications to contrast medium are present, a CT scan without contrast medium of 
chest and MRI of abdomen and pelvis could be used.  
- MRI or CT scan of the brain in patients with a history of asymptomatic brain metastases. 
- Whole body bone scan, if clinically indicated.  
Note: Tumour assessment will not be repeated when already performed within 4 weeks prior to 
Visit 1, Day 1.  
 Physical examination including vital signs (i.e. BP, heart rate, respiratory rate, body 
temperature), height and weight. 
 Blood sample for CTC enumeration before the treatment. 
 Assessment of ECOG PS. 
 12-lead ECG record (pre-dose). 
 12-lead ECG record (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. 

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 
  
 
 
 
 
 
 
 
 
 Dispensing of the patient diary for study treatment compliance. 
 Instruction for MEN1611 administration for the following days at home. 
 Recording of AEs and concomitant medications. 
 Cohort assignment. 
 Study treatment administration, according to the following order: 
- 
Premedication with a corticosteroid and a H1 receptor antagonist 30-60 minutes prior to 
the cetuximab application. 
- 
Cetuximab 400mg/m2 as a 120 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting condition of the first assigned dose 
(48 mg or 32 mg as 3 or 2 capsules BID, respectively). 
Note: Patients will be monitored at the site for occurrence of AE during cetuximab infusion and after 
the end of infusion for at least 1 hour. 
Visit 2 (Day 8), Visit 3 (Day 15) and Visit 4 (Day 22): 
(All assessments can be performed within 48 hours prior to administration of the study treatment at 
site, unless otherwise indicated.) 
 Physical examination including vital signs (i.e. BP, heart rate, respiratory rate, body 
temperature) and weight. 
 Assessment of ECOG PS. 
 12-lead ECG record (pre-dose, ONLY at DAY 15). 
 12-lead ECG record (2 4 hours post first daily MEN1611 dose administration, ONLY at DAY 
15).  
 Blood samples for haematology, coagulation and chemistry. 
 
 
 
 
 
 
  

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 Recording of AEs and concomitant medications. 
 Study treatment administration, according to the following order: 
- 
Premedication with a corticosteroid and a H1 receptor antagonist 30-60 minutes prior to 
the cetuximab application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting condition of the first assigned dose 
(48 mg or 32 mg as 3 or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE during cetuximab infusion and 
after the end of infusion for at least 1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular disorders Grade ≥ 2 are assessed (the 
AE has to be followed until resolution to Grade 1). A dermatological visit shall be performed in case 
skin toxicity Grade ≥ 3 is assessed (the AE has to be followed until resolution to Grade 1). The 
frequency of ophthalmic and dermatological visits can be increased upon Investigator’s judgement. 
 
Cycle 2: 
Visit 1 (Day 1) (+ 5-Day window): 
(All assessments can be performed within 48 hours prior to administration of the study treatment at 
site, unless otherwise indicated.) 
 Physical examination including vital signs (i.e. BP, heart rate, respiratory rate, body 
temperature) and weight. 
 Blood sample for CTC enumeration before the treatment. 
 
 
 Assessment of ECOG PS. 
 12-lead ECG. 
 Blood samples for haematology, coagulation and chemistry including HbA1c. 
 Serum pregnancy test (if applicable). 
 Sample for urinalysis. 
 Dispensing of the patient diary for study treatment compliance. 
 Recording of AEs and concomitant medications. 

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 Study treatment administration, according to the following order: 
- 
Premedication with a corticosteroid and a H1 receptor antagonist 30-60 minutes prior to 
the cetuximab application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting condition of the first assigned dose 
(48 mg or 32 mg as 3 or 2 capsules BID, respectively). 
Note: Patients will be monitored at the site for occurrence of AE during cetuximab infusion and after 
the end of infusion for at least 1 hour. 
Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 22): 
(All assessments can be performed within 48 hours prior to administration of the study treatment at 
site, unless otherwise indicated.) 
 Physical examination including vital signs (i.e. BP, heart rate, respiratory rate, body 
temperature) and weight. 
 Assessment of 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 order: 
- 
Premedication with a corticosteroid and a H1 receptor antagonist 30-60 minutes prior to 
the cetuximab application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting condition of the first assigned dose 
(48 mg or 32 mg as 3 or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE during cetuximab infusion and 
after the end of infusion for at least 1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular disorders Grade ≥ 2 are assessed (the 
AE has to be followed until resolution to Grade 1). A dermatological visit shall be performed in case 
skin toxicity Grade ≥ 3 is assessed (the AE has to be followed until resolution to Grade 1). The 
frequency of ophthalmic and dermatological visits can be increased upon Investigator’s judgement. 

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Cycle 3 up to Cycle 6:  
Visit 1 (Day 1) (+ 5-Day window)  
(All assessments can be performed within 48 hours prior to administration of the study treatment at 
site, unless otherwise indicated.) 
 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: ctDNA levels 
ONLY at Cycle 3 and CTC enumeration ONLY at Cycle 3 and Cycle 5.  
 Tumour assessment using RECIST v1.1 will be performed at Cycle 3 and Cycle 5 (within a 
window of 7 days before the visit date). 
 Sample for urinalysis. 
 Assessment of ECOG PS. 
 12-lead ECG (same technique used at baseline) will be performed ONLY at Cycle 3 and Cycle 
5. 
 Dispensing of the patient diary for study treatment compliance. 
 Recording of AEs and concomitant medications. 
 Study treatment administration, according to the following order: 
- 
Premedication with a corticosteroid and a H1 receptor antagonist 30-60 minutes prior to 
the cetuximab application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting condition of the first assigned dose 
(48 mg or 32 mg as 3 or 2 capsules BID, respectively). 
Note: Patients will be monitored at the site for occurrence of AE during cetuximab infusion and after 
the end of infusion for at least 1 hour. 
Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 22): 
(All assessments can be performed within 48 hours prior to administration of the study treatment at 
site, unless otherwise indicated.) 
 Physical examination including vital signs (i.e. BP, heart rate, respiratory rate, body 
temperature) and weight. 
 Assessment of ECOG PS. 
 Blood samples for haematology, coagulation and chemistry, ONLY at Day 15. 
 Recording of AEs and concomitant medications. 

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 Study treatment administration, according to the following order: 
- 
Premedication with a corticosteroid and a H1 receptor antagonist 30-60 minutes prior to 
the cetuximab application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 
- 
Dispensing of MEN1611 and administration in fasting condition of the first assigned dose 
(48 mg or 32 mg as 3 or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE during cetuximab infusion and 
after the end of infusion for at least 1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular disorders Grade ≥ 2 are assessed (the 
AE has to be followed until resolution to Grade 1). A dermatological visit shall be performed in case 
skin toxicity Grade ≥ 3 is assessed (the AE has to be followed until resolution to Grade 1). The 
frequency of ophthalmic and dermatological visits can be increased upon Investigator’s judgement. 
Cycle 7 Onwards:  
Visit 1 (Day 1) (+ 5-Day window), Visit 2 (Day 8), Visit 3 (Day 15) and Visit 4 (Day 22) 
(All assessments can be performed within 48 hours prior to administration of the study treatment at 
site, unless otherwise indicated.) 
 Physical examination including vital signs (i.e. BP, heart rate, respiratory rate, body 
temperature) and weight. 
 Assessment of ECOG PS. 
 12-lead ECG (same technique used at baseline) at Day 1 of Cycle 7 and then EVERY 2 cycles. 
 Blood samples for haematology, coagulation and chemistry including HbA1c ONLY at 
Day 1. 
 Serum pregnancy test (if applicable) ONLY at Day 1. 
 Sample for urinalysis ONLY at Day 1. 
 Tumour assessment using RECIST v1.1 at Day 1 of Cycle 7 and then EVERY 2 cycles (within 
a window of 7 days before the visit date). 
 Blood sample for CTC enumeration before the treatment ONLY at Day 1 of Cycle 7 and then 
EVERY 2 cycles. 
 Dispensing of the patient diary for study treatment compliance at Day 1. 
 Recording of AEs and concomitant medications. 
 Study treatment administration, according to the following order: 
- 
Premedication with a corticosteroid and a H1 receptor antagonist 30-60 minutes prior to 
the cetuximab application. 
- 
Cetuximab 250mg/m2 as a 60 minutes IV infusion. 

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- 
Dispensing of MEN1611 and administration in fasting condition of the first assigned dose 
(48 mg or 32 mg as 3 or 2 capsules BID, respectively). 
Note-1: Patients will be monitored at the site for occurrence of AE during cetuximab infusion and 
after the end of infusion for at least 1 hour. 
Note-2: An ophthalmic visit shall be performed in case ocular disorders Grade ≥ 2 are assessed (the 
AE has to be followed until resolution to Grade 1). A dermatological visit shall be performed in case 
skin toxicity Grade ≥ 3 is assessed (the AE has to be followed until resolution to Grade 1). The 
frequency of ophthalmic and dermatological visits can be increased upon Investigator’s judgement. 
Note-3: 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). 
 Tumour assessment using RECIST v1.1 will be performed if the last assessment is older than 
8 weeks. 
 Assessment of ECOG PS. 
 Smoking history and current smoking status. 
 Blood samples for haematology, coagulation and chemistry. 
 Sample for urinalysis. 
 Recording of AEs and concomitant medications. 
 Serum pregnancy test (if applicable). 
 ctDNA levels and CTC enumeration assessments. 
Note-1: All patients 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 patient’s withdrawal can replace the End of Study Visit provided that all 
assessment/procedures scheduled for this visit are completed. 
Note-2: Images collected at each tumour assessment time point have to be uploaded into a dedicated 
iMedidata Application according to the manual for retrospective central analysis. 
 
Survival Follow-up: 
After the End of Study Visit, all patients evaluable for efficacy will be followed for survival status 
according to local practice (a visit or a telephone call) every 12 weeks up to the End of Study. 

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8.5.2 
Sample Handling and Shipping Management  
In order to perform PK, genetic, exploratory 
 
 and 
safety analyses, a whole blood volume ranging between 15 and 44 mL, with a maximum amount of 
approximately 62 mL (only at Visit 1 of Cycle 3), needs to be collected per visit. 
Other than safety samples that will be locally analysed, biological samples will be processed at site and 
analysed centrally. All biological samples except safety blood samples collected along the study will 
be stored for a maximum of 10 years from the date of the Last Patient Last Visit. After 10 years, the 
samples will be destroyed (for further details, please refer to the Laboratory Manual). 
8.5.3 
 
MEN1611 plasma concentration-time data will be analysed using a population PK approach. A 
nonlinear mixed effects model will be used to determine population PK parameters and their 
associated variabilities (e.g. apparent systemic clearance [CL/F], V/F, Ka).  

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Individual PK parameters (e.g. AUC, Cmax) will be estimated using a post hoc analysis. 
The modelling strategy is detailed in the PK Data Analysis Plan (DAP). 
Leftover PK sample aliquots could be analysed to further elucidate in-vivo metabolic 
biotransformation of MEN1611. 
8.5.4 
Safety Assessment 
Safety and tolerability endpoints will be derived from the following measurements/evaluations: 
 Incidence, severity as per CTCAE v5.0 grading, seriousness and treatment-causality of 
Treatment Emergent Adverse Events (TEAEs). 
 Frequency of clinically significant abnormalities in: 
- 
Physical examination and vital signs. 
- 
Safety laboratory tests. 
- 
12-lead ECG record. 
- 
Urinalysis. 
8.5.4.1 
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 CRC) 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 CRC specific medical history will include: date of onset of primary tumour, sidedness, histology, 
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 28 days prior to Screening. 
CRC specific medical history shall be collected starting from the primary CRC onset date. 
8.5.4.2 
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. 

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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 or °F. 
8.5.4.3 
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. 
8.5.4.4 
Body Surface Area 
For cetuximab treatment dose, patient’s BSA will be calculated before each administration using the 
most recent patient weight available. If the patient's weight at the beginning of each cycle varies > 10% 
from the last cycle, the dose must be recalculated. The height will be measured at Visit 1 Cycle 1 and 
serves as basis for the calculation of BSA ensuring the correct dose adjustment for cetuximab. Any of 
the established formulas may be used to calculate BSA according ASCO guidelines (40). 
8.5.4.5 
Performance Status Evaluation 
PS evaluation will be performed at each study visit from Screening to End of Study Visit using the 
ECOG status. 
Table 8-7 ECOG Performance Status (PS) 
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 Oncology Group 

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8.5.4.6 
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 patient 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 patient’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 patient 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). 
The lab print-outs should be identified with the patient number. All print-outs should be dated and 
signed by the Investigator and stored in the patient’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 8-8). 

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Table 8-8 Blood and Urine Sample Analyte Listing 
Chemistry 
Serum Virology 
Haematology 
Coagulation  
Urinalysis* 
 
Creatinine 
 
Uric acid 
 
Potassium 
 
Phosphorus 
 
Calcium 
 
Magnesium 
 
CEA 
 
CA19-9 
 
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 
 
HBsAg 
 
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 
 
Activated partial 
thromboplastin 
time and/or 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, CA19-9 = carbohydrate antigen 19-9, CEA = carcinoembryonic antigen, 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, and nitrite. Microscopy will only be performed when required (i.e., red blood cell [RBC], 
white blood cell [WBC], epithelial cells, casts, bacteria, yeast and crystals).  
 

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8.5.4.7 
12-Lead Electrocardiogram 
12-lead ECGs will be performed locally, using standard equipment available at the study sites during 
the Screening Period, prior to study treatment administration, and 2 hours post first daily MEN1611 
dose administration at Visit 1 and Visit 3 of Cycle 1. ECGs will be repeated prior study treatment 
administration on Visit 1 of Cycle 2 and Cycle 3, and then every 2 cycles at Visit 1.  
ECGs will be performed at rest in the supine position. All ECG print-outs should be identified with 
patient 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 patient’s record. Copies of all ECG 
traces will be collected along study duration for future safety analyses.  
8.5.5 
Study Endpoints 
8.5.5.1 
Primary Endpoints 
Step 1 (Identification of Dose for Cohort Expansion): 
 Identification of the dose for the Cohort Expansion, defined as the highest dose level 
(maximum dose tested 48 mg BID, minimal dose tested 32 mg BID) at which no more than 
1 of 6 patients experiences a DLT (see DLT definition) during the DLT assessment window 
(28 days) or the maximum dose judged to be tolerable by the DSC. 
 The DSC will review and evaluate all the available safety data, any DLTs and PK data 
collected during Step 1, in order to confirm the RP2D to be tested in Step 2 (see also Section 
8.7). 
Step 2 (Cohort Expansion Phase): 
 Best ORR defined according to RECIST v1.1 assessment locally performed using 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 patient. 
 
 

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8.5.5.2 
Secondary Endpoints 
 Safety and tolerability:  
- 
Incidence, severity as per CTCAE v. 5.0 grading, seriousness and treatment-causality of 
TEAEs. 
- 
Frequency of clinically significant abnormalities in physical examination, safety laboratory 
tests, urinalysis, vital signs and 12-lead ECG. 
 PK profile: MEN1611 plasma concentration-time data will be analysed using a population PK 
approach. A nonlinear mixed effects model will be used to determine population PK 
parameters and their associated variabilities (e.g. CL/F, V/F, Ka). Individual PK parameters 
(e.g. AUC, Cmax) will be estimated using a post hoc analysis. 
 Disease Control Rate (DCR) defined as percentage of patients whose disease shrinks or 
remains stable over a certain time period. DCR is the sum of the complete, partial and stable 
disease rates according to local assessment.  
 Duration of response defined as time from confirmation of a PR, CR or SD as locally assessed, 
until the disease has been shown to progress following treatment.  
 PFS: Defined as the number of days between the first study treatment administration to the 
date of first documented disease progression as per local assessment, relapse or death from 
any cause. Responding patients and patients who are lost to follow-up are censored at their 
last tumour assessment date. 
 OS: Defined as the number of days between the first study treatment administration and death 
from any cause. 
For the baseline assessment, CT scan or MRI should be performed no more than 4 weeks before the 
start of study treatment. Follow-up assessment will be performed every 2 cycles during study 
treatment starting from Day 1 Cycle 3 (within a window of 7 days before the visit date) 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.  
 
8.5.5.3 
Exploratory Endpoints 

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8.6 Adverse Event Definitions, Monitoring/Recording and Management 
8.6.1 
Definitions 
8.6.1.1 
Adverse Event 
Any untoward medical occurrence in a patient or clinical study patient 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) has a 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 

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and it follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge (AE 
reappearance after drug reintroduction) is not required to fulfil this definition.  
3. Possibly related: The event or laboratory test abnormality (AE) has a reasonable time 
relationship 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. 
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 the existence of a clear alternative 
explanation.  
8.6.1.3 
Treatment-Emergent Adverse Events 
AEs will be categorized as 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 treatment intake, it will be classified as TEAE, 
otherwise it will be classified as non-TEAE. 
8.6.1.4 
Adverse Drug Reactions 
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, 
cetuximab or both given in combination. This means that there are facts (evidence) or arguments to 
suggest a causal relationship. 
ADRs are considered all AEs for which the relationship with any of the IMPs 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: 

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1. Unlikely related 
2. Not related 
8.6.1.5 
Seriousness 
Any untoward medical occurrence that at any dose: 
 Results in death; 
 Is life-threatening; 
 Requires in-patient hospitalisation or prolongation of existing hospitalisation; 
 Results in persistent or significant disability/incapacity; 
 Results in congenital anomaly/birth defect; 
 Is other medically important condition that may jeopardise the patient or may require 
intervention to prevent 1 of the outcomes listed above.  
Note-1: 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 patient 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 had been more severe.  
Any other AE/ADR which is not included in the above definitions will be considered as non-serious. 
Note-2: Hospitalisation lasting less than 24 hours or pre-planned hospitalisation for medical intervention, 
such as study treatment administration or PK sampling time-points, shall not qualify as SAE/Adverse 
Drug Reaction Intensity (Severity). 
Each event will be graded for severity using the classifications of NCI CTCAE v5.0. For events not 
addressed in the NCI CTCAE v5.0 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.   
 
 

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8.6.1.6 
Adverse Drug Reaction Expectedness 
An ADR is considered unexpected when its nature, intensity, or outcome is not consistent with the 
applicable product information provided in the Reference Safety Information document (MEN1611 IB, 
version in force and cetuximab SmPC). 
8.6.1.7 
Serious Unexpected Adverse Reaction 
Any SAE judged by the Investigator or the Sponsor as drug-related (see Section 8.6.1.2) 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, cetuximab or their combination). 
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 date 
of screening informed consent signature to the End of Study Visit. 
The Investigator should manage as AE any laboratory test abnormality (newly occurring after the 
IMP administration or worsening of previously known abnormalities) considered as clinically 
significant as per Investigator’s judgement: i.e. values significantly above or under normal range or 
which require an intervention or diagnostic tests, or may result in the IMP discontinuation. The 
Investigator shall record on the respective eCRF-AE pages any AE, serious or non-serious, whether 
or not thought to be drug-related, observed in or reported by the patient (or relatives/delegates), 
specifying the judgement on the causal relationship with the study treatment. When the investigator 
confirms that all the collected information on any Individual Case Safety Report (ICSR; serious or 
not, related or not) has been entered in the eCRF, an email notification is automatically sent to the 
Sponsor. 
AEs communicated by the patient or by the patient’s relatives or delegates through phone calls, letters 
or emails will also be recorded. In these cases, the Investigator will try to obtain medical confirmation 
and assessment of the occurred AE. 
Any available information and diagnostic measure (laboratory and instrumental tests, procedures, 
etc.) shall also be recorded in the corresponding pages of the eCRF. 
Progression of the disease under study will not be captured as an AE. 
 
 

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8.6.3 
Management of Serious Adverse Events 
8.6.3.1 
Reporting Duties of the Investigator 
The Investigator must record and save all the available information on any ICSR with at least one SAE 
(whether or not deemed related to any of the study treatments) by completing the eCRF-AE pages. 
He/she must also ensure that any concerned eCRF pages containing all the available information at that 
time are updated no later than 24 hours after the first knowledge of the occurrence of the case. 
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).  
The Investigator will be provided with the paper CRF-SAE form to be used only in case of 
breakdown/non availability of the eCRF System. In such case, the Investigator will be responsible for 
sending the paper CRF-SAE form to the SDSM no later than 24 hours after the first knowledge and 
subsequently inserting the data in eCRF as soon as the system works again.  
Whenever the paper CRF-SAE form is used, it must be submitted by email to the Sponsor’s SDSM:  
Sponsor’s SDSM contact details: 
 
Alfons XII, 587 
08918 Badalona (Barcelona), Spain 
Phone: 
 
Mobile: 
 
Email: 
 
For the initial SAE notification, the Investigator should enter at least the following data: 
 AE medical term. 
 Seriousness criteria. 
 Causality assessment.  
 Patient ID (when the paper CRF-SAE forms are used). 
 Reporter’s name and telephone number for clarification (when the paper CRF-SAE forms are 
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 patient’s records at 
the site.  
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 email.  

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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 SDSM. 
Any further significant information and supporting documentation that becomes available (such as 
copies of laboratory reports, tests, procedures, autopsy evidence of the cause of death, etc.) shall be 
provided to the Sponsor’s SDSM, preferably by entering it in the eCRF or by email (in case of eCRF 
unavailability), no later than 24 hours after they become known by the Investigator. 
The Investigator must also comply with the local applicable obligation(s) on the reporting of ADRs 
to the local concerned CA /Ethics Committees (ECs) /IRBs 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, that will be 
responsible for the management of AEs from all the sites in compliance with the applicable regulatory 
requirements (including SAEs and SUSARs management), as well as for all safety communications 
submitted to the sites, CAs and ECs/IRBs accordingly to the procedures described in the 
corresponding study Safety Management Plan (SMP). 
 
Particularly, the Sponsor’s SDSU shall ensure that all relevant information about any SUSAR is 
expeditiously reported to the CAs and ECs/IRBs (following general and local rules and procedures), 
with the below applicable deadlines after the first knowledge (Day 0), intended as the day when the 
Sponsor’s receives the notification of the SUSAR or the monitor is aware of it: 
 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 and supporting documentation that 
subsequently become available is also expeditiously reported as follow-up information no later than 
15 days after the first knowledge 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. 

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When appropriate and applicable as per local regulatory requirements, the Sponsor will circulate the 
relevant new information also to the Investigators. The Sponsor (through the SDSU) will distribute 
the validated Council for International Organization of Medical Sciences (CIOMS) I form or 
MedWatch form + AOSE (Analysis of Similar Events) (for USA) to the investigators (via e-mail) 
with a safety letter, if required by local regulations. 
 
Note-1: For SUSARs occurred in other ongoing studies with MEN1611, if any, the Sponsor will 
comply with the expedited reporting obligations to the ECs, CAs and Investigators involved in 
MEN1611-02 study. 
 
Note-2: The Sponsor will be responsible for expeditiously reporting SUSAR cases attributable to 
cetuximab, following the procedure described in the SMP, and informing the corresponding 
Marketing Authorization Holder (as per SmPC details) of the case and expedited reporting done.            
For SUSARs occurred with non-IMP (e.g. concomitant medication) the post-marketing 
pharmacovigilance rules should be followed according to the requirements of the country of 
occurrence.  
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 MEN1611, to cetuximab or to their combination) in the corresponding 
section of the eCRF, eCRF-AE pages, within 5 calendar days after the first knowledge of the 
occurrence of the event. 
When the site personnel enter a new AE/case in the eCRF, an automatic alert notification will be 
generated and sent to the Sponsor’s SDSM.  
If relevant, all eCRF pages concerning medical history, concomitant medication, laboratory tests and 
any other relevant information will also be retrieved by the Sponsor’s SDSM and saved in the safety 
master file. 
Any further significant information and supporting documentation that become available (such as 
copies of laboratory tests, procedures, etc.) shall also be provided by the Investigator through the 
eCRF or by e-mail in case of eCRF unavailability to the Sponsor’s SDSM. 
In addition, during the clinical study, abnormalities in laboratory analyses, physical examination, 
urinalysis, vital signs and 12-lead ECG (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 

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intervention or diagnostic tests, or may result in the discontinuation of the study treatment), should 
be reported as AEs. All clinically significant abnormalities in laboratory values, physical 
examination, urinalysis, vital signs and 12-lead ECG will be collected and reviewed by the 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 patient or in the female partner of a patient enrolled on the 
study and while participating in the study (occurring during the treatment and follow-up periods). 
The “Pregnancy Exposure Report Form” is distributed to the sites to be used for this purpose. 
In case of pregnancy, the patient will be withdrawn from the study treatment. The Investigator is 
requested to follow each case of pregnancy until the outcome, provided that the female patient or the 
female partner of a male patient enrolled in the study has signed the related pregnancy ICF. 
The form will be sent to the Sponsor’s SDSM by email within 5 days after the Investigator becomes 
aware of the pregnancy and it is to be fully completed and sent again within 5 days after the outcome 
is known, if it is normal (healthy newborn). 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 managed through the paper CRF-SAE form and sent to the Sponsor by 
email. 
8.6.6 
Management of Misuse and Overdose Cases 
Although study drug misuse and overdose are not considered AEs per se, both issues should be 
reported to the Sponsor’s SDSU, even if they may not result in an adverse outcome. In the event of 
overdose, the patient 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 or 
cetuximab) which is more than the assigned dose level for that patient. The corresponding information 
should be entered in the AE page in the eCRF no later than 24 hours since 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. 
In addition, if an AE (serious or non-serious) is associated with an overdose, it will be recorded in the 
AE page in the e-CRF, recording the overdose details. 
If the pharmacy service detects or suspects that an overdose has or may have been administered, they 
should immediately contact the Investigator and the Sponsor (or their delegate) and let them know. 

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8.6.7 
Periodic Safety Reporting 
8.6.7.1 
Annual Safety Reporting (DSUR or IND Annual Report) 
Once a year throughout the clinical study, the Development Safety Update Report (DSUR) will be 
submitted by the Sponsor to the concerned CAs (including Food and Drug Administration [FDA]) 
and ECs, taking into account all new safety information received during the reporting period. 
In Europe, the DSUR will be submitted to CAs and ECs by the SDSU within 60 calendar days after 
the Data Lock Point (DLP). In US, the DSUR will be submitted to the US Agent within 50 calendar 
days after the DLP, who will subsequently submit it to the FDA within 60 calendar days after the 
Data Lock Point (DLP) 
8.6.7.2 
Periodic Line-listings Safety Reporting 
All SUSARs occurred in the MEN1611-02 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 Investigators and EC, 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: In case that 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 patient safety. In general, it could be the case of new events related to the conduct of this 
or other trials with MEN1611 to be likely to affect the safety of patients (e.g.: an 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). In such cases, appropriate actions are to be 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). In any case the Sponsor shall inform the National 
Competent Authority as well as the concerned ECs and participating investigators of any safety issues 
which might materially alter the current benefit-risk assessment of the study IMP.  

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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 patient unless 
ongoing SAEs or non-serious AEs of special interest (as per the DSC) 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-SAE form will be used as 
a backup.  
Patients who discontinued the treatment for safety reasons will be followed-up until the event 
disappears, the patient’s condition stabilises, or until recovery from all toxic effects and longer in case 
of expected delayed toxicity. 
8.7 Data Safety Committee and Safety Monitoring 
In conjunction with the investigators, the Sponsor will constantly monitor the incoming safety data, 
especially TEAEs, SAEs and SUSARs to continuously assess the overall risk/benefit of the patients 
enrolled in this study and to take appropriate actions. 
A DSC 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 DSC is responsible for reviewing and evaluating all the available safety data, any 
DLTs and PK data collected during Step 1 in order to confirm the RP2D to be tested in Step 2. During 
Step 2 of the study, safety and need for dose reductions and/or modifications will continue to be 
monitored for all patients in all cycles and the DSC will review this study in regular meetings (at least 
every 3 months).  
The DSC may also meet in ad hoc meetings at its discretion, as needed in response to events occurring 
in the study. Data will be provided by the Sponsor to the DSC as described in the approved Data 
Review Plan. The Data Review Plan will be finalized under responsibility of the Sponsor before the 
First Patient In.  

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8.8 Blinded Independent Review Committee (BIRC) 
A BIRC will be composed by independent reviewers who will have the aim to evaluate each patient’s 
CT/MRI scans, applying RECIST 1.1 guideline. The details of the execution of the blinded review 
are provided in a separate BIRC Charter. 

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9 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
9.1 Determination of Sample Size 
9.2 Analysis Populations 
DLT population: 
All patients receiving at least 80% of MEN1611 and 75% of cetuximab during Cycle 1 with a Safety 
Follow-up of 28 days after the first administration of the study treatment. Any patient who 
experiences a DLT will also be considered evaluable, regardless of the dose received.  
Patients enrolled in the Dose-confirmation Phase, who are not DLT evaluable, will be replaced. 
Safety population: 
All patients receiving at least 1 dose of MEN1611. 
Efficacy population: 
All eligible patients who receive at least 2 complete treatment cycles and have at least 1 disease 
assessment are to be considered evaluable for efficacy. 
PK population: 
All patients receiving the study treatment and for whom a PK sample is obtained and analysed. 
 
 
 

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9.3 Statistical Analysis 
9.3.1 
Descriptive Statistics 
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% CI), 3rd quartile, Kaplan-Meier survival 
curves and event rate every 28 days. 
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 patient’s variables will be evaluated calculating the appropriate correlation 
coefficient with the respective statistical significance level. 
9.3.2 
Pharmacokinetic Analysis 
PK analysis will be performed on the PK population. All PK variables (i.e. MEN1611 plasma 
concentrations) 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 PK endpoints will be described in the PK DAP. 
 

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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 CTCAE 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. 
9.4 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. 
9.5 Statistical Analysis Plan 
The statistical analysis plan (SAP) will be finalised under responsibility of the Sponsor 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 patient of a 
substantial protocol amendment.  

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10 DATA QUALITY MANAGEMENT 
10.1 Data Collection 
Data collection activities will be carried out under the responsibility of the Sponsor. Patient data will 
be collected using an Electronic Data Capture system (EDC; see Section 10.1.1). Patients will be 
identified by the study identification number (Patient ID), assigned during the Pre-Screening Period.  
The Patient 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 patient 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 iMedidata 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.  
 
 

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10.1.2 
Interactive Web-response System 
IWRS system ClinPhone RTSM, provided by Calyx is a validated system used by the site personnel 
for the patient pre-screening (including assignment of the patient number), kit assignment and patient 
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 Calyx and provided to site. Details on the IWRS provider 
can be found in the specific manual. Some data such as patient 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). 
The IWRS will be developed by Calyx in collaboration with the Sponsor. 
10.1.3 
Patient Diary 
Patients 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 (patient diary) that will be provided by the Sponsor. 
The patient 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 patient for completion. 
10.1.4 
Central Laboratory/Examination Data 
Central laboratories’ data will be managed according to laboratory SOPs and will be transferred to 
Menarini Ricerche S.p.A., Clinical Sciences department for statistics and PK analyses. Sites will 
receive from central laboratories only reports related to PIK3CA, N-K-RAS and BRAF mutational 
analysis of ctDNA. 
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 
Tumour Images Collection 
Images obtained will be uploaded by the site personnel in a dedicated iMedidata application that 
transmits the images to CRO platform for BIRC review. 
The Sponsor will be responsible to set up the study configuration in the iMedidata application for 
images loading based on this study protocol. Site staff will access the platform using the same 
credentials as to access the eCRF. 
Details on images management will be available in a site manual before imaging transmission starts. 

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Result of the central reading will be transmitted to the Sponsor according to the Data Transfer 
Agreement document. 
10.1.6 
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. 
10.2 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. 
10.3 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/patients’ medical records, 
laboratory notes, radiological images, ECG records, patient’s diary, patients’ identification forms and 
pharmacy dispensing records. Study sites will also maintain 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, analyse, 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 

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precautions within the constraints of the applicable regulatory requirements to maintain the 
confidentiality of patient 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 patient’s record. 
 
10.4 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, patient’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 
starting from the date of the Screening informed consent signature to the End of Study, 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 patient-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 Sponsor’s 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. 
12.1 Archiving of Electronic Documentation/Data 
Duplicate electronic media such as CDs/DVDs (1 for routine access and 1 for back-up) containing 
the patient 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 dedicated 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 

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Final Version 5.0 
15 May 2023 
 
 
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Clinical Trial Protocol 
EudraCT No.: 2019-003727-38   
 
Study Code MEN1611-02 
Final Version 5.0 
15 May 2023 
 
 
152 of 155 
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Final Version 5.0 
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