Conditions: Unresectable Hepatocellular Carcinoma (HCC)
Keywords: Unresectable Hepatocellular Carcinoma (HCC)
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 31
Healthy volunteers: no

Brief summary:
This is a Phase I/II, open-label, non-randomized, multicenter study to explore safety, tolerability and antitumor activity of NMS-01940153E as single agent in adult patients with unresectable hepatocellular carcinoma (HCC) previously treated with systemic therapy.

The Phase I portion is designed as a dose-escalation study in sequential cohorts of patients aimed to obtain the maximum tolerated dose (MTD) that is defined based on the dose limiting toxicities (DLTs) observed in the first cycle of treatment.

The Phase II portion is designed as a two-stage study with an interim analysis for futility and stopping criteria for unacceptable toxicity to assess the antitumor activity of NMS-01940153E in adult patients with unresectable HCC previously treated with systemic therapy measured as objective response rate.

Detailed description:

Arms:
arm 1: Phase I: Patients will be allocated to sequential cohorts of progressively higher dose levels of NMS-01940153E based on the presence of Dose Limiting Toxicities (DLT).

Phase II: Patients will be treated at the recommended Phase II dose (RP2D) defined in the Phase I portion.

Interventions: intervention 1: NMS-01940153E
Intervention descriptions: intervention 1: Route of administration: intravenous (IV) solution

Protocol document:
Prot_002.pdf: 
Document Type:  
Final Protocol 
Document Date:  
09 January 2023 
Study Title:  
Study on Safety and Efficacy of NMS-01940153E in Adult Patients 
With Unresectable Hepatocellular Carcinoma (HCC) Previously 
Treated With Systemic Therapy  
Protocol Reference Number:  MPSA-153-001  
NCT Number:  
NCT05630937 
 


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 Phase I/II study on safety and efficacy of NMS-01940153E in 
adult patients with unresectable hepatocellular carcinoma (HCC) 
previously treated with systemic therapy 
Project Code: 
M912 
Sponsor: 
Nerviano Medical Sciences S.r.l. 
Therapeutic Area: 
Oncology 
Substance Identifier: 
NMS-01940153E 
Protocol Number: 
MPSA-153-001 
EudraCT Number: 
2020-001002-26 
Status: 
Final 
Protocol Version Number: 
5 
Including Amended Information as per: 
 
Amendment No. 
Date 
Country 
Site(s) 
1 
28 Jan 2021 
Italy 
All 
NA 
28 Jan 2021 
Spain 
All 
2 
18 Feb 2022 
Italy, Spain 
All 
3 
30 Jun 2022 
Italy, Spain 
All 
4 
09 Jan 2023 
USA, Italy, Spain 
All 
 
This document contains confidential information belonging to the Sponsor. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such 
information in confidence and not to disclose it to others (except where required by applicable 
law), nor to use it for unauthorized purposes. In the event of actual or suspected breach of this 
obligation, the Sponsor should be promptly notified. 
 
 
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SPONSOR REFERENCES AND APPROVAL 
 
Sponsor Name: 
Nerviano Medical Sciences, S.r.l. 
Sponsor Address: 
Viale Pasteur, 10 
20014 Nerviano (Milano) 
Italy 
 
 
Sponsor  
Medical Expert: 
 
 
 
Sponsor  
Statistician: 
  
 
 
Sponsor 
Representative: 
 
 
 
 
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INVESTIGATOR’S SIGNATURE 
 
 
Title 
Phase I/II study on safety and efficacy of NMS-01940153E in adult 
patients with unresectable hepatocellular carcinoma (HCC) 
previously treated with systemic therapy 
Protocol Number 
MPSA-153-001 
Version Number 
5 
Date 
09 January 2023 
 
 
 
I declare that I will carry out the study in accordance with the referenced protocol, the ICH 
E6 R2 (Good Clinical Practices), Declaration of Helsinki and in accordance to local legal and 
regulatory requirements. 
 
 
 
 
Investigator’s Name 
 
Investigator’s Title 
Investigational Site Name 
 
 
Investigational Site Address 
 
 
Investigator’s Signature 
 
Date 
 
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TABLE OF CONTENTS 
1. SUMMARY ................................................................................................................... 9 
1.1. Protocol Identifiers................................................................................................... 9 
1.2. Background Information and Study Rationale ........................................................ 9 
1.3. Trial Objectives and Endpoints .............................................................................. 11 
1.4. Study Design and Methods .................................................................................... 12 
1.5. Subject Selection .................................................................................................... 17 
1.6. Schedule of Events ................................................................................................. 20 
2. ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 21 
3. BACKGROUND INFORMATION AND STUDY RATIONALE ............................. 24 
3.1. Disease background ............................................................................................... 24 
3.2. Study rationale ....................................................................................................... 25 
3.3. Non-clinical data .................................................................................................... 26 
3.4. Toxicology ............................................................................................................. 26 
3.5. Clinical data ........................................................................................................... 27 
3.6. Safety results .......................................................................................................... 28 
3.7. Efficacy results....................................................................................................... 28 
4. TRIAL OBJECTIVES AND ENDPOINTS ................................................................. 29 
4.1. Objectives .............................................................................................................. 29 
4.1.1. Primary Objective ............................................................................................ 29 
4.1.2. Secondary Objective(s) .................................................................................... 29 
4.1.3. Explorative Objective: ..................................................................................... 29 
4.2. Endpoints ............................................................................................................... 29 
4.2.1. Primary Endpoint ............................................................................................. 29 
4.2.2. Secondary Endpoint(s) ..................................................................................... 30 
4.2.3. Exploratory Endpoint: ...................................................................................... 30 
5. TRIAL DESIGN AND DESIGN RATIONALE ......................................................... 31 
5.1. Treatment administration: ...................................................................................... 31 
5.2. Phase I Dose Escalation ......................................................................................... 32 
5.2.1. Definition of DLTs .......................................................................................... 33 
5.2.2. DLT window .................................................................................................... 34 
5.2.3. Patient replacement .......................................................................................... 35 
5.2.4. Definition of MTD and RP2D ......................................................................... 35 
5.3. Phase II................................................................................................................... 35 
6. SUBJECT SELECTION .............................................................................................. 37 
6.1. Subject Inclusion Criteria ...................................................................................... 37 
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6.2. Subject Exclusion Criteria ..................................................................................... 38 
7. SCHEDULE OF EVENTS .......................................................................................... 41 
8. ENROLLMENT PROCEDURES ................................................................................ 50 
8.1. Screening Procedures ............................................................................................. 50 
8.2. Enrollment procedures ........................................................................................... 51 
9. TREATMENT .............................................................................................................. 51 
9.1. Product ................................................................................................................... 51 
9.1.1. Description ....................................................................................................... 51 
9.1.2. Drug Preparation/Administration/Dispensing ................................................. 51 
9.1.3. Procedure for Handling Drug Spills ................................................................ 52 
9.1.4. Storage and Stability ........................................................................................ 52 
9.1.5. Source of drug .................................................................................................. 52 
9.1.6. The study product ............................................................................................ 52 
9.2. Treatment Administration ...................................................................................... 53 
9.2.1. Treatment Dose and Schedule ......................................................................... 53 
9.2.2. Duration of Treatment...................................................................................... 53 
9.2.3. Dose Modifications .......................................................................................... 54 
9.2.3.1. Dose Reductions/Treatment discontinuations ........................................... 54 
9.2.3.2. Re-treatment Criteria and Cycle Delay ..................................................... 54 
9.2.4. Extension Treatment ........................................................................................ 56 
9.2.5. Overdose Instructions ...................................................................................... 56 
9.2.6. Unblinding ....................................................................................................... 56 
9.2.7. Concomitant Medications and Other Therapy ................................................. 56 
9.2.7.1. Antiemetics Support .................................................................................. 57 
9.2.7.2. Antidiarrheal Support ................................................................................ 57 
9.2.7.3. Hematopoietic Support .............................................................................. 57 
9.2.7.4. Prophylaxis for Polysorbate 80 intolerance ............................................... 58 
9.2.7.5. Other Permitted Concomitant Medications ............................................... 58 
9.2.7.6. Other Anticancer or Experimental Therapy .............................................. 58 
9.2.7.7. Concomitant Radiotherapy ........................................................................ 58 
10. SUBJECT WITHDRAWAL FROM STUDY PARTICIPATION ............................ 59 
11. ASSESSMENTS ........................................................................................................ 61 
11.1. Timing of Assessments ........................................................................................ 61 
11.2. Disease Assessments ............................................................................................ 61 
11.2.1. TNM Staging ................................................................................................. 61 
11.2.2. Barcelona Clinic Liver Cancer (BCLC) Staging System .............................. 61 
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11.3. Efficacy Assessments........................................................................................... 62 
11.3.1. Tumor Imaging .............................................................................................. 62 
11.3.1.1. Central Imaging Facility .......................................................................... 63 
11.3.1.2. Measurability of Tumor Lesions ............................................................. 64 
11.3.1.3. Recording Tumor Measurements ............................................................ 65 
11.3.1.4. Target Lesions Tumor Response ............................................................. 67 
11.3.1.5. Non Target Lesions Tumor Response ..................................................... 69 
11.3.1.6. New Lesions ............................................................................................ 70 
11.3.1.7. Confirmation of Tumor Response ........................................................... 71 
11.3.1.8. Determination of Overall Response by RECIST (version 1.1) ............... 71 
11.3.1.9. Determination of Overall Response by mRECIST .................................. 72 
11.3.1.10. Best Overall Response ........................................................................... 73 
11.4. Outcomes Research Assessments ........................................................................ 75 
11.5. Safety Assessments .............................................................................................. 75 
11.5.1. Adverse Event Assessment ............................................................................ 75 
11.5.1.1. Definition of Adverse Events .................................................................. 75 
11.5.1.2. Unexpected Adverse Event ..................................................................... 76 
11.5.1.3. Eliciting Adverse Event Information ....................................................... 76 
11.5.1.4. Adverse Event Reporting Period ............................................................. 77 
11.5.1.5. Adverse Event Follow Up after the End of the Reporting Period ........... 77 
11.5.1.6. Relationship to the Investigational Medicinal Product ............................ 77 
11.5.1.7. Reporting Requirements .......................................................................... 78 
11.5.1.8. Recording Adverse Events in the Case Report Forms ............................ 79 
11.5.1.9. Grading of Adverse Event Severity ......................................................... 79 
11.5.1.10. Exposure In Utero .................................................................................. 80 
11.5.2. Laboratory Safety Assessments ..................................................................... 81 
11.5.3. Other Safety Assessments .............................................................................. 83 
11.6. Other Assessments ............................................................................................... 84 
11.6.1. Blood sampling .............................................................................................. 84 
11.6.2.1. Bioanalytical method ............................................................................... 86 
11.6.3. Urine Sampling .............................................................................................. 87 
11.6.4. Exploratory Assessments ............................................................................... 87 
11.6.4.1. cfDNA Sampling ..................................................................................... 87 
12. STATISTICAL METHODS ...................................................................................... 88 
12.1. Sample Size Calculation ...................................................................................... 88 
12.2. Definition of Analyzed Study Populations .......................................................... 88 
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12.3. Analyses ............................................................................................................... 89 
12.3.1. Study Conduct and Subject Disposition ........................................................ 89 
12.3.2. Baseline Characteristics and Treatment Group Comparability ..................... 90 
12.3.3. Treatment Administration/Compliance ......................................................... 90 
12.3.4. Efficacy Analyses .......................................................................................... 90 
12.3.4.1. Primary Efficacy Endpoint ...................................................................... 90 
12.3.4.2. Secondary Efficacy Endpoints ................................................................. 90 
12.3.5. Outcomes Research Analyses ........................................................................ 91 
12.3.6. Safety Analyses .............................................................................................. 91 
12.3.7. Analyses of Other Endpoints ......................................................................... 92 
12.3.7.1. Alpha-Fetoprotein as Surrogate Marker of Efficacy ............................... 92 
12.3.7.2. Pharmacokinetic ...................................................................................... 92 
12.3.7.3. Translational Research ............................................................................ 95 
12.4. Interim Analysis Plan ........................................................................................... 95 
12.5. Data Monitoring Committee ................................................................................ 96 
13. END OF THE TRIAL ................................................................................................ 96 
14. QUALITY CONTROL AND QUALITY ASSURANCE ......................................... 97 
15. DATA HANDLING AND RECORD KEEPING ...................................................... 97 
15.1. Electronic Case Report Forms (eCRFs) ............................................................... 97 
15.2. Record Retention ................................................................................................. 98 
15.3. Confidentiality of Clinical Trial or Study Documents ......................................... 98 
16. ETHICS ...................................................................................................................... 98 
16.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........... 98 
16.2. Ethical Conduct of the Trial ................................................................................. 99 
16.3. Informed Consent Process ................................................................................... 99 
16.4. Personal Data Protection .................................................................................... 100 
17. SPONSOR DISCONTINUATION CRITERIA ...................................................... 100 
18. DISSEMINATION AND PUBLICATION OF RESULTS ..................................... 100 
19. REFERENCES ......................................................................................................... 101 
 
TABLES 
Table 1. DLT criteria ........................................................................................................... 34 
Table 2. Phase I Schedule of Events ................................................................................... 41 
Table 3. Investigational Assessments details for Phase I .................................................... 44 
Table 4. Phase II Schedule of Events .................................................................................. 46 
Table 5. Investigational Assessments details for Phase II ................................................... 49 
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Table 6. Dose Reductions/Treatment Discontinuations for NMS-01940153E Based on the 
Worst Grade (as per NCI CTCAE Criteria, Version 5.0) Observed During a 
Treatment Cycle and in the Prior Treatment Cycle ................................................ 55 
Table 7. Definitions for T, N, M ......................................................................................... 61 
Table 8. Definitions for prognostic groups .......................................................................... 62 
Table 9. Response Criteria by RECIST 1.1* ....................................................................... 72 
Table 10. Response Criteria in mRECIST* ........................................................................ 73 
Table 11. Best overall response when confirmation of CR and PR required ...................... 74 
Table 12. Grading of Adverse Event Severity for events  not reported in the CTCAE v 5.0
 ................................................................................................................................ 80 
Table 13. Phase I PK Blood Sample Collection .................................................................. 85 
Table 14. Phase II PK Blood Sample Collection ................................................................ 86 
Table 15. PK Urine Sample Collection ............................................................................... 87 
 
APPENDICES 
Appendix 1. ECOG Performance Status ..................................................................... 104 
Appendix 2. Child Pugh Score and Classification ...................................................... 105 
Appendix 3. Contra-indicated drugs ........................................................................... 106 
Appendix 4. Concomitant treatments to be used with caution ................................... 107 
Appendix 5. The Distribution of Active Bone Marrow in the Adult .......................... 108 
Appendix 6. Recommended Effective Contraception ................................................ 109 
 
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1. SUMMARY 
1.1. Protocol Identifiers 
Therapeutic Area: 
Oncology 
Product: 
NMS-01940153E 
Indication: 
Unresectable Hepatocellular Carcinoma (HCC) 
Protocol Number: 
MPSA-153-001 
Title of Study: 
Phase I/II study on safety and efficacy of NMS-01940153E in adult patients with 
unresectable hepatocellular carcinoma (HCC) previously treated with systemic therapy  
1.2. Background Information and Study Rationale 
Primary liver cancer is the 6th most common neoplasm and among the leading cause of cancer-related deaths 
worldwide. Hepatocellular carcinoma (HCC) constitutes 80–90% of all primary liver cancers. The incidence is 
increasing and will soon surpass one million annual cases worldwide. 
At early stages of HCC (BCLC stage 0/A), treatment strategies are potentially curative and include liver 
resection, liver transplantation, and ablation. At intermediate stages (BCLC stage B), palliative locoregional 
therapies such as transarterial chemoembolization (TACE) remain the gold standard for treatment. However, 
most HCC cases are diagnosed at advanced stages (BCLC stage C) when curative therapies or TACE are no 
longer indicated. 
Until recently, sorafenib was the only approved systemic therapy for HCC. The therapeutic landscape changed 
remarkably in 2017 with the approval of regorafenib as second-line treatment for patients with HCC who have 
been previously treated with sorafenib. When well tolerated, treatment with sorafenib followed by regorafenib 
(at radiologic progression on sorafenib) results in a median OS of 26 months. However, when this sequence is 
not possible due to lack of efficacy or intolerance to these drugs, the prognosis remains poor. In 2018, based on 
a Phase III non-inferiority trial, lenvatinib was approved in Japan, Europe and the USA as a first-line treatment 
in HCC. In 2019, cabozantinib and ramucirumab received regulatory approval for HCC patients previously 
treated with sorafenib. In addition, the United States Food and Drug Administration (FDA) approved 
pembrolizumab and, recently, ipilimumab in combination with nivolumab, for use in the second line following 
sorafenib. 
A phase III trial of atezolizumab combined with bevacizumab demonstrated a significantly better overall survival 
and progression-free survival outcomes than sorafenib in patients with advanced unresectable HCC not 
previously treated with systemic therapy. The combination was approved in 2020 and is now the preferred 1st 
line treatment option both for NCCN and ESMO guidelines. 
Regardless of the availability of therapeutic agents in first and second lines, the failure of systemic treatment 
remains a major therapeutic challenge and relapsed/refractory HCC still represents an area of unmet medical 
need. Patients with good performance status and compensated liver function who progress after all approved 
treatments are considered suitable for new investigational drugs or strategies. 
NMS-01940153E, 
also 
known 
as 
S81694 
(from 
now 
on 
called 
NMS-01940153E), 
is 
a 
dihydropyrazoloquinazoline derivative, potent small molecule inhibitor of Monopolar Spindle 1 kinase (MPS1 
which is also known as TTK kinase). MPS1 is a dual tyrosine/threonine kinase expressed only in proliferating 
cells. Upon activation by phosphorylation, MPS1 plays a critical role in the control of mitosis regulating the 
Spindle Assembly Checkpoint (SAC) through proper kinetochore recruitment of other essential SAC proteins.  
Most solid tumors are characterized by complex chromosome rearrangements. Aneuploidy is a common feature 
of cancer cells: approximately 90% of solid tumors are aneuploid, with the majority (> 70%) having a gain rather 
than a loss of chromosomes. MPS1 has been found highly expressed in a number of tumors of different origins. 
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Non-clinical data 
In tumor cells exposed to NMS-01940153E, anti-proliferative activity is associated with the expected 
mechanism of action of an MPS1 inhibitor. It causes mitotic checkpoint override, accelerates mitosis, induces 
chromosomal misalignment, and promotes aneuploidy, apoptosis and cancer cell death, accompanied by 
reduction of mitotic markers such as phospho-histone H3 and MPS1 auto-phosphorylation. 
In vitro, NMS-01940153E is active on a broad panel of cancer cell lines. 
 
 
. 
Nonclinical safety of NMS-01940153E was characterized in single-dose toxicity studies after IV administration 
in rats, dogs and monkeys and in repeated toxicity studies after once weekly IV administration for 4 weeks in 
rats and monkeys. In the pivotal GLP 4-week toxicity studies the major target organs observed following the 
repeated administration of NMS-01940153E were the haemolymphopoietic system (HLP) in rats and monkeys, 
the intestinal tract in rats and the male reproductive organs particularly in rats at high doses. In addition, injection 
site alterations were seen in both species. 
NMS-01940153E induced haemolysis was observed in vitro on human blood at high concentrations (≥ 320 µM); 
no haemolysis occurred up to a concentration of 200 µM. 
According to the toxicity studies, NMS-01940153E safety profile was considered manageable, with target organ 
toxicity in line with its pharmacological mechanism of action. 
Clinical data 
NMS-01940153E originated in Nerviano Medical Sciences and was licensed out to Servier in 2013. Servier 
conducted a phase I, First in Human trial (FIH), with NMS-01940153E as single-agent, in patients with 
advanced/metastatic solid tumors (EudraCT 2014-002023-10) and a Phase I-II study of NMS-01940153E in 
combination with paclitaxel in patients with advanced/metastatic breast cancer (EudraCT 2017-002459-27). In 
2019 Servier decided to stop the clinical development of NMS-01940153E due to internal portfolio decisions 
and the compound was returned to Nerviano Medical Sciences. 
The Phase I, FIH study, was a dose-escalation study of NMS-01940153E administered to sequential cohorts of 
adult patients with advanced/metastatic solid tumors; the primary objective of the study was to define the 
Maximum Tolerated Dose (MTD) and the associated Dose-Limiting Toxicities for NMS-01940153E 
administered as IV infusion on days 1, 8, 15 in repeated 4-week cycles. 
The study was stopped before the primary objective was met. Thirty-eight patients were treated according to 
nine different dose levels (4, 6, 9, 13.5, 20, 30, 45, 67.5 and 135 mg/m2/week); among 36 patients evaluable for 
first cycle Dose Limiting Toxicities, 3 DLTs were reported: grade 3 anemia, at 4 mg/m2/week; grade 4 
hypertensive crisis, at 20 mg/m2/week; grade 3 fatigue, at 135 mg/m2/week. 
The most frequent treatment emergent adverse events (TEAEs) reported in at least 15% of patients were fatigue 
(57.9%), anaemia (44.7%), nausea (31.6%), decreased appetite (28.9%), constipation, pain, vomiting (23.7% 
each), cough (21.1%), diarrhea (18.4%) and dyspnea (15.8%). 
The most frequent TEAEs related to NMS-01940153E reported in at least 10% of patients were anaemia 
(36.8%), fatigue (28.9%), nausea (21.1%), decreased appetite (15.8%), neutropenia (13.2%) and diarrhea 
(10.5%). 
Thirty-six out of 38 treated patients were evaluable for efficacy; one patient, with metastatic clear renal cell 
cancer, achieved a durable complete tumour response (CR); 13 patients showed stable disease (SD), including 
2 patients with HCC.Although only 2 patients with HCC refractory to multiple prior therapies were enrolled in 
the study, both remained stable for 6 months and one of them had a transient decrease in tumor size. On these 
grounds, we hypothesize that monotherapy treatment in previously treated patients with advanced HCC might 
be further explored. 
Refer to the Investigator's Brochure for current clinical status. 
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1.3. Trial Objectives and Endpoints 
Primary Objective: 
• 
To determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of NMS-
01940153E administered as single agent to adult patients with unresectable hepatocellular carcinoma (HCC) 
previously treated with systemic therapy (Phase I). 
• 
To assess the anti-tumor efficacy of NMS-01940153E administered as single agent to adult patients with 
unresectable hepatocellular carcinoma previously treated with systemic therapy (Phase II). 
Secondary Objectives: 
• 
To define the safety and tolerability profile of NMS-01940153E. 
• 
To evaluate the pharmacokinetics of NMS-01940153E and its main metabolite NMS-03593478 in plasma 
and, limited to Phase I, also in urine. 
• 
To evaluate additional measures of antitumor efficacy of NMS-01940153E. 
Exploratory Objective: 
• 
To explore correlation among Alpha-Fetoprotein (AFP) levels changes with NMS-01940153E exposure and 
clinical outcomes; 
• 
To explore correlation among baseline tumoral and clinical prognostic factors with clinical outcome; 
• 
To explore the potential correlation of selected molecular alterations in circulating free DNA (cfDNA) at 
baseline with clinical outcome. 
Primary Endpoints: 
• 
Drug related Dose Limiting Toxicities (DLTs) (Phase I). 
• 
Objective Response Rate (ORR). The ORR will be calculated as the proportion of evaluable patients who 
have achieved, as best overall response (BOR), confirmed complete response (CR) or partial response (PR) 
measured by investigator-assessed RECIST 1.1 (Phase II). 
Secondary Endpoints: 
• 
Overall safety profile of NMS-01940153E characterized by type, severity (graded using NCI CTCAE 
Version 5.0), duration of the adverse events (AEs) and laboratory and ECG abnormalities, and relationship 
of the AEs to study treatment in the first and subsequent cycles of therapy. 
• 
Pharmacokinetic parameters of NMS-01940153E and its main metabolite NMS-03593478 in plasma and 
urine (urine only in Phase I). 
• 
Objective Tumor Response (Partial and Complete Response) as measured by investigator-assessed RECIST 
1.1 (Phase I). 
• 
Objective response rate  as measured by investigator-assessed mRECIST (Phase II). 
• 
Duration of response (DoR) as measured by investigator-assessed RECIST 1.1. and investigator-assessed 
mRECIST. 
• 
Progression Free Survival, including landmark analyses, as measured by investigator-assessed RECIST 1.1. 
• 
Overall survival (OS). 
Exploratory Endpoint: 
• 
Evaluation of AFP plasma levels; 
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• 
Evaluation of tumoral and other clinical prognostic features at baseline; 
• 
Assessment of selected molecular alterations in circulating free DNA (cfDNA) at baseline 
 
1.4. Study Design and Methods 
Study Design:  
This is a Phase I/II, open-label, non-randomized, multicenter study to explore safety, tolerability and antitumor 
activity of NMS-01940153E as single agent in adult patients with unresectable HCC previously treated with 
systemic therapy. 
An independent Data Safety Monitoring Board (DSMB) will provide study oversight through periodic safety 
evaluations and make recommendations on study progress in the transition from Phase I to Phase II and at the 
planned interim analysis for the futility of Phase II. 
The Phase I portion is designed as a dose-escalation study in sequential cohorts of patients aimed to obtain the 
MTD that is defined based on the DLTs observed in the first cycle of treatment. The selection of the starting 
dose and the dose escalation scheme is based on the safety information gained in the FIH study (EudraCT 2014-
002023-10) and in consideration of the possible different tolerability in patients with compromised liver. 
Once the MTD is identified and the safety profile of NMS-01940153E has been reviewed by the Investigators, 
the Sponsor and the independent DSMB and is considered adequate based on the entire Phase I data available, 
the Phase II portion of the study started. The Phase II portion is designed as an exploratory two stage study with 
an interim analysis for futility and stopping criteria for unacceptable toxicity to assess the antitumor activity of 
NMS-01940153E in adult patients with unresectable HCC previously treated with systemic therapy measured 
as objective response rate.  
Treatment:  
NMS-01940153E is supplied as labeled type I glass vials containing 30 mg/vial of powder for solution for 
infusion. Each labeled vial (primary packaging) is packaged in a labeled single small carton (secondary 
packaging). 
Patients will receive treatment with NMS-01940153E administered as intravenous (IV) infusion for 3 
consecutive weeks on days 1, 8, 15 followed by 1 week of rest, in a 28-day cycle. The duration of infusion will 
be dependent on the total dose to be administered: 
• 
1 hour infusion if ≤ 255 mg are administered 
• 
1 hour 30 minutes infusion if > 255 mg but < 375 mg are administered 
Within one cycle, in case the patient cannot be retreated on the day foreseen because of toxicity, the dose will 
be skipped and the patient will be retreated at the next foreseen time-point. 
Dose reduction/omission is foreseen based on toxicities observed. 
Patients that cannot be retreated for any reason within 1 week from day 28 (up to day 35) will go off-treatment, 
unless the investigator believes treatment continuation is in the patient’s best interest. In this case a maximum 
delay of 2 weeks (up to day 42) will be allowed. Otherwise patients may continue on investigational drug until 
disease progression, unacceptable toxicity, withdrawal of consent by the patient or other discontinuation criteria 
described in the protocol are met. 
Phase I Dose Escalation 
The safety profile of NMS-01940153E administered IV on days 1, 8, 15 every 4 weeks has been characterized 
in the FIH, dose escalation study, conducted in adult patients with advanced/metastatic solid tumors up to the 
dose of 135 mg/m2/week. This dose was not defined as MTD in study 2014-002023-10 (EudraCT), since only 1 
patient experienced DLT (Grade 3 fatigue) out of 6 evaluable patients. 
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Considering the possible different tolerability in patients with compromised liver, the proposed starting dose for 
the Phase I portion of the study is 100 mg/m2/week, which is an intermediate dose level between the highest 
(135 mg/m2/week) and the next lower dose level (67.5 mg/m2/week) tested in the FIH study. According to the 
observed safety profile, dose increments of 25-35% will be applied to the proposed starting dose, until the MTD 
is reached. In presence of unacceptable toxicity observed at 100 mg/m2/week, a lower dose level by 25-35% may 
be tested. 
Patients experiencing DLT during the DLT window can be retreated according to the time delay and dose 
modification schema. 
No intra-patient dose escalation will be allowed. 
Phase II 
In the Phase II portion of the study, patients will be treated at the RP2D defined in the Phase I portion, as starting 
dose. 
Phase I Dose Escalation 
A conventional 3+3 study design with inter-individual dose-escalations will be adopted. Patients will be 
allocated to sequential cohorts of progressively higher dose levels of NMS-01940153E based on the presence of 
Dose Limiting Toxicities (DLT). 
At each dose level, a minimum of 3 patients will be included. 
If 0/3 patients experiences first cycle DLT, the next cohort will start one dose level higher. 
If 1/3 patients experiences first cycle DLT, up to three more patients will receive the study medication at the 
same dose level; if 1/6 patients experiences first cycle DLT the next cohort will start one dose level higher. 
If ≥2/3 or ≥2/6 patients experience DLTs in the first cycle of treatment, the MTD is considered to have been 
exceeded. Three more patients will be entered at the previous dose level (if only 3 patients were previously 
treated at that prior dose) or, in case the MTD is exceeded at the starting dose level, six patients will be entered 
to a lower dose level. 
Only one dose level will be open for enrollment at any time.  
The first patient enrolled on a dose level should be observed for DLT for at least 2 weeks before entering any 
other patient at that dose level. 
In absence of 1st cycle DLT in the first patient, the third patient can be enrolled at any time. 
In presence of 1st cycle DLT in the first patient, the third patient can be enrolled only after the second patient has 
completed the first cycle without DLT. 
In case a cohort needs to be expanded to more than 3 patients, the additional patients can be enrolled 
simultaneously. 
All patients must be observed for one cycle before subsequent patients are enrolled at the next higher dose level. 
If a patient fails to receive at least 66% of the first cycle of treatment, for reasons other than treatment-related 
toxicities, an additional patient must be enrolled at the same dose level. 
After the completion of each cohort, available safety and pharmacokinetic (PK) data will be reviewed and new 
dose levels will be decided jointly by the Investigators and the Sponsor. 
Definition of DLTs 
For this protocol, a DLT will be defined as any of the following events for which the relationship to NMS-
01940153E cannot be definitely excluded. Toxicities are to be graded according to the NCI CTCAE version 
5.0. 
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Hematological toxicities 
Neutropenia 
Grade 4 lasting >7 days or 
Grade 4 of any duration associated with Grade >2 
infection 
Febrile neutropenia 
ANC <1000/mm3 and a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature 
of >38 degrees C (100.4 degrees F) for more than one 
hour. 
Thrombocytopenia 
Grade 3 associated with any grade bleeding or 
Grade 4  
Anaemia 
Grade > 4 
Non-Hematological toxicities 
Nausea, vomiting or diarrhea 
Grade >3 despite optimal treatment 
Signs of potential severe drug-induced liver injury as 
assessed according to Hy's law 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 ULN and total bilirubin >2 
ULN in the absence of cholestasis (alkaline 
phosphatase [ALP] <2 ULN) and no other reason can 
be identified. 
Any other non-hematological toxicities;  
- Grade ≥ 3 toxicities unless clear alternate etiology 
is documented by the investigator except:  
- asymptomatic Grade 3 electrolyte changes 
that can be successfully supplemented (e.g., 
hypokalemia) and resolve/recover to baseline 
within 72 hours  
- Grade 3 fatigue that improves to ≤ Grade 2 
in no more than 5 days  
- alopecia 
Other significant toxicity 
Failure to complete the first cycle of treatment with at 
least 66% of the planned total dose due to toxicity 
possibly related to the study medication 
- 
Failure to start Cycle 2 for more than 1 week (day 36 
or later) due to persistent Grade ≥ 2 toxicities possibly 
related to the study medication, excluding fatigue 
- 
Any toxicity that is possibly related to the study 
medication and requires the withdrawal of 
the patient 
from the study during the DLT observation period 
- 
Any on-study death not clearly due to the underlying 
disease or extraneous causes 
- 
DLT window 
The DLT window is defined as the time interval between the day of the first dose administration in Cycle 1 and 
the day of the first dose administration in Cycle 2 which is expected to be 28 days or up to 35 days in case of 
dose delay. For patients who do not receive Cycle 2, 35 days will be the time interval considered for the 
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evaluation of DLT, unless no toxicities are observed or recovery of toxicities occurs earlier or unless the patient 
has disease progression and/or starts a new anti-cancer therapy earlier. 
Definition of MTD and RP2D 
The MTD is the dose level at which 0/6 or 1/6 patients experience DLT in the first cycle of treatment with the 
next higher dose having at least 2/3 or 2/6 patients encountering DLT. Effectively, the MTD is the highest dose 
associated with first cycle DLT in < 33% of patients. 
This dose or an inferior one may be the dose recommended for further Phase II investigation (RP2D). 
Phase II 
In the Phase II portion, patients will receive, as starting dose, the RP2D defined in the Phase I portion of the 
study.  
The Phase I part of the trial ended on May 30th, 2022 with the declaration of an RP2D of 100 mg/m2/week, and 
the study has already received a unanimous recommendation from an independent Data Safety Monitoring Board 
(DSMB) to continue the trial, moving to Phase II study. 
The RP2D of 100 mg/m2/week, 3 of 4 weekly schedule, is justified based on safety, efficacy and pharmacokinetic 
considerations.  The trend of dose-related neutropenia as the major safety feature points to the 100 mg/m2/week 
level as more tractable relative to 135 mg/m2 (refer to full safety summaries in the IB).  In terms of anti-tumor 
activity, the fact that, out of 6 evaluable, one confirmed RECIST partial response (despite one missed dose during 
the first two cycles) plus one highly prolonged stable disease were observed at 100 mg/m2 as well as, out of 4 
evaluable, 2 patients with substantial AFP reduction were observed points to reasonable activity at this dose 
level.  Furthermore, pharmacokinetics at the 100 mg/m2 dose level are in a meaningful range relative a 
continuous mouse tumor stabilization model predicting 0.2 uM average concentration threshold relative to the 
100 mg/m2 mean Cmax in HCC patients which is 7 fold higher at 1.35 uM and with AUC just slightly below 
the mouse threshold, 32.5 uM*h versus 35.  Refer to IB for full PK descriptions.  RECIST response and AFP 
reductions were observed at the 135 mg/m2/w level and PK was slightly higher but overall the anti-tumor pattern 
at 135 was similar to 100 mg/m2.  Therefore, overall, the 100 mg/m2 level is justifiable as the RP2D. 
Patients will be enrolled in continuous, and continuously evaluated for endpoints, with a futility analysis and 
stopping criteria for unacceptable toxicity performed as described in Section 12. The enrollment will be stopped 
in the event of futility as described in Section 12, with no more than 20 subjects treated overall until non-futility 
can be declared, if appropriate. For the safety monitoring, if two or more patients on study experience Grade 4 
adverse events the study will be put on hold to evaluate whether to continue or if additional risk mitigation is 
warranted.   In any case, the Sponsor may stop or pause enrollments any time during the study based on safety, 
efficacy or strategic reasons. 
Statistical Methods: 
Analysis Sets 
The following analysis sets are defined according to ICH E9 guidelines. 
Phase I Dose Escalation 
Enrolled Set (ES): this population will include all patients who are enrolled in Phase I part, regardless of whether 
patients receive study treatment or not. This population will be evaluated in the analysis of patients’ disposition. 
Treated Set (TS): this set will include all enrolled patients who take at least one dose of NMS-01940153E. This 
population will be evaluated in the analysis of patients’ disposition, baseline characteristics, treatment exposure, 
safety and efficacy. 
Dose-Limiting Toxicity Evaluable Set (DLTES): this set will include all patients who receive in the first cycle at 
least 66% of study drug, unless the reason for non-compliance is drug-related toxicity, and undergo a DLT 
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assessment within the DLT window. Patients not fulfilling one or more of the aforementioned criteria will not 
be considered evaluable for MTD determination and will be substituted. 
Phase II 
Enrolled Set (ES): this population will include all patients enrolled in Phase II, regardless of whether patients 
receive study treatment or not. This population will be evaluated in the analysis of patients’ disposition. 
Treated Set (TS): this set will include all enrolled patients who actually receive at least one dose of NMS 
01940153E. This population will be evaluated in the analysis of patients’ disposition, baseline characteristics, 
treatment exposure and safety. 
Evaluable Set (ES): this is the patient population for the primary efficacy analysis. This set will include patients 
of the TS who have measurable disease at baseline assessed according to RECIST 1.1 and at least one tumor 
evaluation on treatment, unless they die before the first tumor on-treatment assessment, in which case they will 
be considered treatment failure. 
Primary Endpoint 
Phase I Dose escalation 
The primary endpoint, i.e. first cycle DLT, will be evaluated in the DLT Evaluable Set. All enrolled patients 
who received at least one dose of NMS-01940153E will be included in the analysis of safety. 
Phase II  
The primary endpoint, i.e. the ORR and its confidence interval (CI), will be evaluated in the Evaluable Set as 
the proportion of patients who have achieved as best overall response, confirmed complete response or partial 
response  as defined by investigator-assessed RECIST 1.1. 
Secondary Efficacy Endpoints 
Objective response rate as measured by investigator-assessed mRECIST, and its CI will be provided for Phase 
II part only. 
Duration of response, Progression Free Survival and Overall Survival will be provided for both phases. Time-
to-event endpoints will be also summarized using Kaplan Meier (KM) curves and further characterized in terms 
of median and landmark estimates with the corresponding CI, for Phase II part only. 
Safety analysis 
Safety analyses will be carried out on the Treated Set by assigned dose level and overall for phase I part and 
overall for phase II part. 
For both phases, adverse events and laboratory assessments will be scored according to the NCI CTCAE (version 
5.0) grading system. The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code the 
reported adverse events. 
Pharmacokinetic analysis 
Phase I Dose Escalation 
The pharmacokinetics of NMS-01940153E and its metabolite NMS-03593478 in plasma and urine will be 
assessed by standard non-compartmental analysis. The following pharmacokinetic parameters will be provided 
on both Day 1 and Day 15: maximum concentration (Cmax) and related time of achievement (Tmax), last 
detectable concentration (Clast) and related time of observation (Tlast), area under concentration versus time up 
to 168 hours (dosing interval), half-life of the terminal phase (t½,z), plasma clearance (CL), volume of 
distribution (Vss) and renal clearance (CLR). 
Phase II 
For PK plasma samples collected during Phase II, a sparse sampling procedure will be adopted. 
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Details of the sampling procedures as well as population PK model development description and population PK 
data analysis will be detailed in the population PK Statistical Analysis Plan. 
Pharmacokinetic data from Phase II portion of the study will be analyzed using mixed-effect modeling approach. 
Data may be also pooled with PK data from previous Phase I studies. 
The objective of the population pharmacokinetic data analysis will be to describe the pharmacokinetics of NMS-
01940153E in the subject population and explore the role of demographic and pathophysiological covariates 
influencing the pharmacokinetics of the compound. 
Sample Size Determination: 
An overall sample size of approximately 55 patients may be anticipated considering both phases of the study. 
For the Phase I, approximately 12-15 treated patients may be expected. Since the trial design foresees that 
sequential dose-escalation steps are applied to cohorts of 3 to 6 patients up to the identification of the MTD, the 
number of patients who will be enrolled and treated may vary, depending upon the toxicity observed that will 
influence cohort size and number of dose levels tested. 
For the Phase II, the investigator-assessed objective response rate will be the primary outcome measure. The 
sample size is based on precision considerations for the estimate of the primary efficacy endpoint. A single-
group design will be used to obtain a one-sided 95% lower-limit confidence interval for a single proportion. The 
sample proportion is assumed to be 0.3. To produce a confidence interval with a distance from the sample 
proportion to the lower limit of no more than 0.12, 38 patients will be needed.  
A lower bound of 18% for ORR by RECIST 1.1 would be meaningful relative to second line therapies in HCC.  
The emergence of atezolizumab with bevacizumab in first line has obscured true current second line outcomes 
with regorafenib, lenvatinib or sorafenib but it is logical to assume second line ORR would be no better relative 
to the pre-atezolizumab/bevacizumab era in which sorafenib was the first line standard.  Prior to the 
atezolizuman/bevacizumab era, regorafenib in second line showed ORR of 11% by mRECIST and cabozantinib 
of 4%, nivolumab 15%, pembrolizumab 18% and apatinib 10.7% assessed by RECIST 1.1.  Therefore, in the 
third line setting following failure of atezolizumab/bevacizumab in first line followed by TKI in second line, and 
where current third line standards are not yet defined, it is reasonable to expect historical ORR no higher than 
18%. Accounting for a 10% proportion of non-evaluable patients, up to 43 patients could be required for 
completing the trial, however, the Phase II part of the study will not enroll beyond 40 subjects unless discussed 
and agreed with FDA or relevant health authority based on emerging response rates. 
Interim Analyses: 
In the Phase II part of the study an interim evaluation for futility will be undertaken as soon as the first 10 
evaluable patients will be enrolled and the data for primary efficacy endpoint analysis will be available including 
observations through at least 3 months with at least 1 on-treatment tumor assessment by RECIST 1.1. If less 
than 1 responder i.e. patients who achieved CR or PR as best overall response, are observed, the trial will be 
terminated for futility.  This futility decision must be taken before 20 subjects total are enrolled otherwise 
enrollment will pause at 20 subjects until non-futility can be declared (if applicable).   If at least 1 unconfirmed 
or confirmed responder is observed and there are no safety limitations, patients’ enrollment will continue and 
proceed up to an overall enrollment of 38 evaluable patients or 40 total patients.  
For the safety monitoring, if two or more patients on study experience Grade 4 adverse events the study will be 
put on hold to evaluate whether to continue or if additional risk mitigation is warranted.  The independent DSMB 
will review the interim results and provide a recommendation on the study progress.   
1.5. Subject Selection 
Subject Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for 
enrollment into the study:  
1. Histological, cytological or radiological diagnosis of HCC, according to the American Association for the 
Study of Liver Diseases (AASLD) / European Association for the Study of the Liver (EASL) criteria, in 
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subjects that are refractory or not able to tolerate the standard therapy, or subjects for whom the standard 
therapy is not considered appropriate by the physician. 
2. The subject has disease that is not amenable to a curative treatment approach (e.g., transplant, surgery, 
radiofrequency ablation) and unsuitable for or refractory to locoregional treatments (e.g., TACE). 
3. At least one uni-dimensional measurable lesion by CT or MRI according to RECIST 1.1 which is either not 
previously treated by local therapy or, if treated, it has clearly progressed before the subject is recruited. 
4. Phase I only: subjects must have disease relapsed or refractory to the standard of care treatment not 
exceeding 3 lines of prior systemic treatment. Subjects intolerant to previous treatment with TKIs are 
eligible. 
Phase II: subjects must have disease relapsed or refractory to the standard of care treatment including an 
immunocheckpoint inhibitor as first line and at least a tyrosine kinase inhibitor, not exceeding 3 lines of 
prior systemic treatment. 
 
A minimum of 14 days of treatment with prior TKI would be required to qualify as line of therapy. 
5. Child-Pugh score ≤6 (class A, see Appendix 2). 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
7. Age 18 years old on day of consent. 
8. No history of liver transplantation or not listed for high urgent transplantation. 
9. Required laboratory data: 
Absolute neutrophil count (ANC) 
 1,500/mm3 (> 1.5 x 109/L) 
Platelets 
 60,000/mm3 ( 60.0 x 109/L) 
Hemoglobin* 
 10.0 g/dL 
Albumin 
 3.0 g/dL ( 30 g/L) 
Total serum bilirubin 
 1.5 x ULN and no more than 2 mg/dl, unless 
abnormality considered due to Gilbert’s syndrome 
Creatinine clearance** 
> 60 mL/min  
ALT/AST  
 5 x ULN 
INR 
 1.5 
*Transfusions of red blood cells or other hemocomponents not allowed within 72 h before treatment start. 
**Calculated using the Cockroft-Gault equation (mL/min): (140 – age) x weight (kg) / (serum creatinine 
[mg/dL]× 72) for males. (For females multiply by 0.85) 
10. In case of active hepatitis B (HBV) or chronic HIV infection the patient should receive antiviral therapy per 
local standard of care. 
11. Patients must use effective contraception or abstinence. Female subjects must be surgically sterile or, if 
subjects of childbearing potential, must agree to use effective contraception (see Appendix 6) or 
abstinence during the period of therapy and in the following 180 days after discontinuation of study 
treatment. Male subjects must be surgically sterile or must agree to use effective contraception or abstinence 
during the period of therapy and in the following 90 days after discontinuation of study treatment. 
12. With the exception of alopecia, resolution of all acute toxic effects of any prior systemic therapy, surgery 
or radiotherapy to NCI CTC (Version 5.0) Grade ≤1 or to the baseline laboratory values as defined in 
Inclusion Criteria Number 9. 
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13. Able and willing to comply with scheduled visits, therapy plans, and laboratory tests required in this 
protocol. 
14. Signed and dated IEC-approved Informed Consent Form indicating that the subject is aware of the neoplastic 
nature of his/her disease and has been informed of the procedures to be followed, the investigational nature 
of the therapy, potential benefits, side effects, discomforts, risks and alternative treatments. 
Subject Exclusion Criteria: The presence of any of the following will exclude a subject from study 
enrollment: 
1.  Known fibrolamellar HCC or mixed hepato-cholangiocarcinoma. 
2. Subjects with untreated or incompletely treated gastro-esophageal varices with bleeding or at high risk for 
bleeding are excluded with the following clarification: subjects with history of prior variceal bleeding must 
have been treated with adequate endoscopic therapy without any evidence of recurrent bleeding for at least 
6 months prior to study entry and must be stable on optimal medical management (e.g. non-selective beta 
blocker, proton pump inhibitor) at study entry.  
3. Subjects with QTcF interval ≥480 milliseconds or with risk factors for torsade de pointes (e.g., heart failure, 
uncontrolled hypokalemia, family history of long QT syndrome) or receiving treatment with concomitant 
medications known to prolong the QT/QTc interval that cannot be replaced with another treatment. 
4. Ascites defined as CTCAE Grade ≥2. Subjects who have been on a stable medication regimen for at least 2 
months to manage ascites are eligible if they show ascites Grade <2. Subjects with clinically undetectable 
ascites who are Child A with detectable ascites at CT/MRI are eligible. 
5. Uncontrolled high blood pressure (systolic blood pressure, SBP >150 mmHg and/or diastolic blood 
pressure, DBP >95 mmHg, despite optimal treatment, on at least 2 out of 3 determinations repeated at 30 
minutes interval and done in case that the first one meets the criterion for exclusion). 
6. Direct-Acting Antivirals (DAA) at the time of treatment start; previous HCV treatment with DAAs is 
allowed. 
7. Clinical evidence of hepatic encephalopathy. 
8. Known brain metastases or evidence of leptomeningeal disease. 
9. Known history of allergic reactions to polysorbate 80. 
10. Any of the following in the past 6 months: myocardial infarction, uncontrolled cardiac arrhythmia, unstable 
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular 
accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis (except chronic/stable 
portal vein thrombosis). 
11. Major surgery, other than diagnostic surgery, within 4 weeks before treatment start. 
12. Any anticancer agent within 4 weeks or, in absence of toxicity, 5 half-lives (within 6 weeks for nitrosureas, 
mitomycin C and liposomal doxorubicin) before treatment start. 
13. Radiation therapy within 4 weeks or radionuclide treatment (e.g., I-131 or Y-90) within 6 weeks before 
treatment start. 
14. Untreated uncontrolled bacterial, viral, or fungal infections including acute HIV infection or  acquired 
immunodeficiency syndrome (AIDS), untreated uncontrolled HBV, untreated uncontrolled HCV, untreated 
uncontrolled concomitant HBV and HCV; patients who are seropositive following HBV vaccine are 
eligible. 
15. Subjects under treatment with therapeutic dose of anticoagulants (e.g., warfarin or warfarin-related agents, 
low-molecular weight heparin, or similar agent such as anti Xa and anti-thrombin agents) or antiplatelet 
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agents (e.g., clopidogrel) or with coagulation disorders. Aspirin at dose up to 100 mg is permitted. 
Prophylaxis with anticoagulants is allowed to meet the INR value range as cited in inclusion criterion 9. 
16. Uncontrolled diabetes mellitus. 
17. Pregnant or breast-feeding women. 
18. Known second malignancy that is progressing or requiring active treatment. Exceptions include adequately 
treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri. 
19. Current enrollment or participation in another interventional clinical trial. 
20. Clinically significant respiratory or metabolic diseases uncontrolled by medication. 
21. Subjects with active alcohol and/or substances abuse. 
22. Any known organ dysfunction, serious illness, acute or chronic medical or psychiatric condition, or 
laboratory abnormality which, in the Investigator’s opinion, may increase the risk associated/interfere with 
study participation, or with the interpretation of the results. 
23. Subjects who, within 7 days prior to the first NMS-01940153E intake, are receiving or received strong 
inducers of FMO1 and FMO3. 
24. Subjects who are receiving sensitive CYP3A4 substrates, CYP3A4 and BCRP substrates with narrow 
therapeutic index (NTI). 
1.6. Schedule of Events 
See protocol Section 7 
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2. ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BCLC 
Barcelona clinic liver cancer 
BCRP 
Breast cancer resistance protein 
BOR 
Best overall response 
BSA 
Body surface area 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CI 
Confidence interval 
CL 
Clearance 
Clast 
Last detectable concentration 
CLR 
Renal clearance 
Cmax 
Maximum concentration 
CR 
Complete response 
CRF 
Case report form 
CT scan 
Computed Tomography 
CTCAE 
Common terminology criteria for adverse events 
CYP 
cytochrome 
DAA 
Direct-acting antivirals 
DBP 
Diastolic blood pressure 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
ECOG PS 
Eastern cooperative oncology group performance 
status 
eCRF 
Electronic case report form 
EoT 
End of treatment 
FIH 
First in human 
FMO 
Flavin-containing monooxygenase 
FU 
Follow up 
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G 
Grade 
Gamma()-GT 
Gamma-glutamyl transferase 
GCD 
Global Clinical Development 
G-CSF 
Granulocyte-Colony stimulating factor 
h 
Hour 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator brochure 
ICF 
Informed consent form 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IV 
Intravenous 
K 
Potassium 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical dictionary for regulatory activities 
MPS1 
Monopolar spindle 1 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
Na 
Sodium 
NCI 
National cancer institute 
NE 
Not evaluable 
NMS 
Nerviano Medical Sciences 
NTI 
Narrow therapeutic index 
ORR 
Overall response rate 
OS 
Overall survival 
P 
Phosphorus 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
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PLT 
Platelet 
PR 
Partial response 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumours 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
SAC 
Spindle assembly checkpoint 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SOC 
System organ class 
t1/2, z 
Half-life of the terminal phase 
TACE 
Transarterial chemoembolization 
TEAE 
Treatment emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
TTK 
Tyrosine/threonine kinase 
ULN 
Upper limit normal 
USA 
United State of America 
Vss 
Volume of distribution 
WBC 
White blood cell 
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3. BACKGROUND INFORMATION AND STUDY RATIONALE 
3.1. Disease background 
Primary liver cancer is the 6th most common neoplasm and among the leading cause of cancer-
related deaths worldwide. Hepatocellular carcinoma (HCC) constitutes 80-90% of all primary 
liver cancers [1, 2]. 
The incidence is increasing and will soon surpass one million annual cases worldwide with 
an age-adjusted incidence of 10.1 cases per 100,000 person-years. In 2019 the estimated 
incidence in US was 42.030 new cases/year diagnosed with estimated disease related deaths 
of 31.780. The disease is more frequent in males than in females, in the ratio of 2.4:1 [1, 2]. 
According to the Italian Cancer Registry, in 2018 12.800 new cases of HCC were documented 
in Italy. The prognosis of the disease is poor with a 5-years survival rate of only 18-20% based 
on US and Italian cancer registry data [1, 2]. 
HCC most common etiological factor in the world is hepatitis B virus (HBV) infection. The 
worldwide incidence is heterogeneous because of the variable prevalence of risk factors. 
Almost 80% of HCC cases occur in sub-Saharan Africa and eastern Asia and the major risk 
factors here are hepatitis B and aflatoxin exposure, whereas hepatitis C and Non-alcoholic 
fatty liver disease (NAFLD) is the primary risk factor in the USA, Europe, and Japan. The 
development of cirrhosis is associated with high risk for developing HCC [3, 4]. 
Coexistence of cancer and cirrhosis in HCC is an essential hallmark that has shaped clinical 
trial design over the time and is outlined in the Barcelona Clinic Liver Cancer (BCLC) 
algorithm. 
The BCLC staging system is an effective, integrated system that takes into account the patient 
performance status (PS), tumor burden, vascular involvement, potential hepatic dysfunction, 
and portal hypertension [5]. 
At early stages of HCC (BCLC stage 0/A), treatment strategies are potentially curative and 
include liver resection, liver transplantation, and ablation. At intermediate stages (BCLC stage 
B), palliative locoregional therapies such as transarterial chemoembolization (TACE) remain 
the gold standard for treatment. However, most HCC cases are diagnosed at advanced stages 
(BCLC stage C) when curative therapies or TACE are no longer applicable [5]. 
Data available in the literature highlight the need to limit prior locoregional therapies in these 
patients to avoid irreversible deterioration of liver function or general health status and switch 
to systemic therapy if no response is observed after TACE. Despite the advances in disease 
care and treatment strategies, patients with advanced HCC still present a poor survival 
outcome [6-7]. 
Until recently, sorafenib, an oral multikinase inhibitor, was the only approved systemic 
therapy for HCC. The first Phase III trial of sorafenib versus placebo demonstrated a 
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significant, yet modest improvement in median overall survival (OS; 10.7 vs. 7.9 months, 
respectively; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.55–0.87; p < 0.001) 
[8,9]. 
The therapeutic landscape changed remarkably in 2017 with the approval of regorafenib as 
second-line treatment for patients with HCC who have been previously treated with sorafenib. 
In the Phase III trial, regorafenib moderately improved median OS over placebo (10.6 months 
vs. 7.8 months; HR, 0.63; 95% CI: 0.50–0.79; p < 0.0001) and progression-free survival (PFS; 
3.1 months vs. 1.5 months; HR, 0.46; 95% CI: 0.37–0.56; p < 0.0001). When well tolerated, 
treatment with sorafenib followed by regorafenib (at radiologic progression on sorafenib) 
results in a median OS of 26 months. However, when this sequence is not possible, due to 
lack of efficacy or intolerance to these drugs, the prognosis remains poor [10 - 13]. 
The Phase III trial of lenvatinib demonstrated non-inferiority to sorafenib in the first-line 
treatment of advanced HCC, with a median OS of 13.6 months compared to 12.3 months, 
respectively (HR, 0.92; 95% CI: 0.79–1.06). Based on these data, in 2018 lenvatinib was 
approved in Japan, Europe and the USA as a first-line treatment in HCC [12 - 13]. 
In 2019, also cabozantinib and ramucirumab received regulatory approval for HCC patients 
previously treated with sorafenib. In addition, the United States Food and Drug 
Administration (FDA) approved pembrolizumab and, recently, ipilimumab in combination 
with nivolumab, for use in the second line following sorafenib [12, 13]. 
A Phase III trial of atezolizumab combined with bevacizumab demonstrated significantly 
better overall survival and progression-free survival outcomes than sorafenib in patients with 
advanced unresectable HCC not previously treated with systemic therapy. The combination 
was approved in 2020 and is now the preferred 1st line treatment option [14] both for NCCN 
and ESMO guidelines. Despite the availability of these new therapeutic options, the overall 
survival of patients with HCC who have failed a first-line therapy remains dismal, in the range 
of only 8-10 months in randomized studies [12-14]. 
Regardless of the availability of therapeutic agents in first and second lines, the failure of 
systemic treatment remains a major therapeutic challenge and relapsed/refractory HCC still 
represents an area of unmet medical need. 
Patients with good performance status and compensated liver function who progress after all 
approved treatments are considered suitable for new investigational drugs or strategies. 
3.2. Study rationale 
NMS-01940153E, also known as S81694 (from now on called NMS-01940153E), is a 
dihydropyrazoloquinazoline derivative, potent small molecule inhibitor of Monopolar Spindle 
1 kinase (MPS1 which is also known as TTK kinase). MPS1 is a dual tyrosine/threonine 
kinase expressed only in proliferating cells. Upon activation by phosphorylation, MPS1 plays 
a critical role in the control of mitosis regulating the Spindle Assembly Checkpoint (SAC) 
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through proper kinetochore recruitment of other essential SAC proteins. The SAC complex 
regulates a mitotic mechanism required for proper chromosome alignment, influencing the 
stability of the kinetochore-microtubule interaction and ensuring that cells do not divide until 
all sister chromatids correctly align to the metaphase plate. 
Most solid tumors are characterized by complex chromosome rearrangements. Aneuploidy is 
a common feature of cancer cells: approximately 90% of solid tumors are aneuploid, with the 
majority (> 70%) having a gain rather than a loss of chromosomes. MPS1 has been found 
highly expressed in a number of tumors of different origins. 
3.3. Non-clinical data 
In tumor cells exposed to NMS-01940153E, anti-proliferative activity is associated with the 
expected mechanism of action of an MPS1 inhibitor. It causes mitotic checkpoint override, 
accelerates mitosis, induces chromosomal misalignment, and promotes aneuploidy, apoptosis 
and cancer cell death, accompanied by reduction of mitotic markers such as phospho-histone 
H3 and MPS1 auto-phosphorylation. 
In vitro, NMS-01940153E is active on a broad panel of cancer cell lines. Particularly high 
sensitivity was observed in 
 
 hepatocellular carcinoma cell lines, whereas normal cell lines resulted to be less 
affected by the treatment. Confirming the slow dissociation rate of NMS-01940153E, a 
relatively brief period of exposure to the compound is sufficient to cause cancer cell death. 
In hepatocellular carcinoma cell lines, single agent antiproliferative activity was observed. 
Moreover, MPS1 is expressed in all tested HCC cell lines.  
In vivo, in various xenograft or transgenic tumor models 
 
 after intravenous (IV) administration, the compound 
demonstrated significant tumor growth inhibition, up to 95% with an intermittent schedule at 
well-tolerated doses from 15 to 30 mg/kg [15]. 
3.4. Toxicology 
Nonclinical safety of NMS-01940153E was characterized in single-dose toxicity studies after 
IV administration in rats, dogs and monkeys and in repeated toxicity studies after once weekly 
IV administration for 4 weeks in rats and monkeys. In the pivotal GLP 4-week toxicity studies 
the major target organs observed following the repeated administration of NMS-01940153E 
were the haemolymphopoietic system (HLP) in rats and monkeys, the intestinal tract in rats 
and the male reproductive organs particularly in rats at high doses. In addition, injection site 
alterations were seen in both species. 
NMS-01940153E was not genotoxic in the Ames test but, as expected based on its mechanism 
of action, induced micronuclei in human peripheral lymphocytes in vitro. 
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NMS-01940153E induced haemolysis was observed in vitro on human blood at high 
concentrations (≥ 320 µM); no haemolysis occurred up to a concentration of 200 µM. 
NMS-01940153E was not irritating to the skin of rabbits while it induced severe ocular 
irritation following the application to the rabbit of 100 mg/eye for 1 hour. 
In the Safety pharmacology investigations, a dose-related inhibition of the IKr potassium 
channel was observed in the hERG assay with a calculated inhibitory concentration 50 (IC50) 
of 13 µM (about 13- to 650-fold the anti-proliferative IC50 and well above the Cmax 
measured in vivo). In a telemetry-monitored cardiovascular study in monkeys, the dose of 4 
mg/kg induced a transient moderate increase in arterial pressure but had no effect on heart 
rate, ECG intervals (including QT and QTc) and body temperature. 
According to the toxicity studies, NMS-01940153E safety profile was considered 
manageable, with target organ toxicity in line with its pharmacological mechanism of action 
[15]. 
3.5. Clinical data 
NMS-01940153E originated in Nerviano Medical Sciences and was licensed out to Servier in 
2013. Two clinical studies were performed by Servier. A Phase I, First in Human trial (FIH) 
was conducted with NMS-01940153E as single-agent, in patients with advanced/metastatic 
solid tumors (EudraCT 2014-002023-10); a Phase I-II study of NMS-01940153E in 
combination with paclitaxel was conducted in patients with advanced/metastatic breast cancer 
(EudraCT 2017-002459-27). In 2019 Servier decided to stop the clinical development of 
NMS-01940153E due to internal portfolio decisions and the compound was returned to 
Nerviano Medical Sciences. 
The Phase I, FIH study, was a dose-escalation study of NMS-01940153E administered to 
sequential cohorts of adult patients with advanced/metastatic solid tumors who had exhausted 
standard treatment options or for whom no standard treatment was available. The objective of 
the study was to define the Maximum Tolerated Dose (MTD) and the associated Dose-
Limiting Toxicities for NMS-01940153E administered as IV infusion on days 1, 8, 15 in 
repeated 4-week cycles [16]. 
The study started in September 2015 and was stopped on July 2019, following the Sponsor’s 
(Servier) decision to stop the development of NMS-01940153E as a single agent. As a 
consequence, the primary objective of the study (to define the Maximum Tolerated Dose) was 
not met. 
Overall 39 patients were enrolled and 38 received treatment with NMS-01940153E at nine 
different dose levels: 4 (6 patients), 6 (3 patients), 9 (3 patients), 13.5 (4 patients), 20 (6 
patients), 30 (3 patients), 45 (3 patients), 67.5 (4 patients), and 135 mg/m2/wk (7 patients). 
The median age at study entry was 58.5 years; ECOG performance status was 0 in 16 patients 
(42.1%) and 1 in 22 (57.9%). 
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The most frequent cancer types at study entry were: cancers of the gastrointestinal tract 
(23.7%), cancers of lung (13.2%), cancer of head and neck (10.5%), sarcomas of the soft 
tissue and bone (7.9%), benign and malignant mesothelioma, cancer of the breast and cancers 
of the endocrine system (5.3% each) [16]. 
3.6. Safety results 
Among 36 patients evaluable for first cycle Dose Limiting Toxicities, 3 DLTs were reported: 
grade 3 anemia, at 4 mg/m2/week; grade 4 hypertensive crisis, at 20 mg/m2/week; grade 3 
fatigue, at 135 mg/m2/week [16]. 
The most frequent treatment emergent adverse events (TEAEs) reported in at least 15% of 
patients were fatigue (57.9%), anaemia (44.7%), nausea (31.6%), decreased appetite (28.9%), 
constipation, pain, vomiting (23.7% each), cough (21.1%), diarrhea (18.4%) and dyspnea 
(15.8%) [16]. 
The most frequent TEAEs related to NMS-01940153E reported in at least 10% of patients 
were anaemia (36.8%), fatigue (28.9%), nausea (21.1%), decreased appetite (15.8%), 
neutropenia (13.2%) and diarrhea (10.5%) [16]. 
Among the 4 patients treated at 67.5 mg/m2/week, the TEAE related to NMS-01940153E 
reported were nausea (2 patients G1), anemia (1 patient G2), decreased appetite (1 patient 
G1), fatigue (1 patient G1) and platelet count decreased (1 patient G3) [16]. 
Among the 7 patients treated at 135 mg/m2/week, the TEAE related to NMS-01940153E 
reported were anemia (1 patient G3, 3 patients G2), neutropenia (4 patients G3), decreased 
appetite (2 patients G2, 1 patient G1), diarrhoea (2 patients G2, 1 patient G1), fatigue (1 
patient G3, 1 patient G2), nausea (1 patient G2, 1 patient G1), haemolysis (1 patient G1), 
keratitis (1 patient G3), mucosal inflammation (1 patient G3) and pain (1 patient G2) [16]. 
3.7. Efficacy results 
The exploration of efficacy was a secondary endpoint for the study and based on objective 
tumour response as defined by the Response Evaluation Criteria in Solid Tumours (RECIST 
version 1.1) [17]. 
The best overall response (BOR) was defined as the best response recorded from the start of 
the investigational drug until the end of treatment, according to Investigator’s assessments. 
Out of the 39 enrolled patients, 3 patients were excluded from the efficacy analysis due to: 
absence of measurable disease at baseline, no dose of NMS-01940153E received, no on 
treatment tumour assessment performed. Out of the 36 patients evaluable for efficacy, one 
patient could not be evaluated since he/she died before the first scheduled tumour assessment. 
Out of the 35 patients for whom a BOR was assessed, one patient, with metastatic clear renal 
cell cancer, achieved a complete tumour response, with response duration of 112.7 weeks; 13 
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patients showed stable disease, including 2 patients with HCC. The duration of the 
stabilization ranged from 6.43 (censored observation) to 67.29 weeks, with a median duration 
of 24.29 weeks (95%CI: 12.29-67.29). 
Although only 2 patients with HCC refractory to multiple prior therapies were enrolled in the 
study, both remained stable for 6 months while on NMS-01940153E and one of them, treated 
at 135 mg/m2/week, had a transient decrease in tumor size. On these grounds, we hypothesize 
that monotherapy treatment in previously treated patients with advanced HCC might be 
further explored. 
4. TRIAL OBJECTIVES AND ENDPOINTS 
4.1. Objectives 
4.1.1. Primary Objective 
• To determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose 
(RP2D) of NMS-01940153E administered as single agent to adult patients with 
unresectable hepatocellular carcinoma (HCC) previously treated with systemic therapy 
(Phase I). 
• To assess the anti-tumor efficacy of NMS-01940153E administered as single agent to 
adult patients with unresectable hepatocellular carcinoma previously treated with systemic 
therapy (Phase II). 
4.1.2. Secondary Objective(s) 
• To define the safety and tolerability profile of NMS-01940153E. 
• To evaluate the pharmacokinetics of NMS-01940153E and its main metabolite NMS-
03593478 in plasma and, limited to Phase I, also in urine. 
• To evaluate additional measures of antitumor efficacy of NMS-01940153E. 
4.1.3. Explorative Objective: 
• To explore correlation among Alpha-Fetoprotein (AFP) levels changes with NMS-
01940153E exposure and clinical outcomes; 
• To explore correlation among baseline tumoral and clinical prognostic factors with 
clinical outcome; 
• To explore the potential correlation of selected molecular alterations in circulating free 
DNA (cfDNA) at baseline with clinical outcome. 
4.2. Endpoints  
4.2.1. Primary Endpoint 
• Drug related Dose Limiting Toxicities (DLTs) (Phase I). 
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• Objective Response Rate (ORR). The ORR will be calculated as the proportion of 
evaluable patients who have achieved, as best overall response (BOR), confirmed 
complete response (CR) and partial response (PR) measured by investigator-assessed 
RECIST 1.1 (Phase II). 
4.2.2. Secondary Endpoint(s) 
• Overall safety profile of NMS-01940153E characterized by type, severity (graded using 
NCI CTCAE Version 5.0), duration of the adverse events (AEs) and laboratory and ECGs 
abnormalities, and relationship of the AEs to study treatment in the first and subsequent 
cycles of therapy. 
• Pharmacokinetic parameters of NMS-01940153E and its main metabolite NMS-
03593478 in plasma and urine (urine only in Phase I). 
• Objective Tumor Response (Partial and Complete Response) as measured by investigator-
assessed RECIST 1.1 (Phase I). 
• Objective response rate  as measured by investigator-assessed mRECIST (Phase II). 
• Duration of response (DoR) as measured by investigator-assessed RECIST 1.1. and 
investigator-assessed mRECIST 
• Progression Free Survival, including landmark analyses, as measured by investigator-
assessed RECIST 1.1. 
• Overall survival (OS). 
4.2.3. Exploratory Endpoint: 
• Evaluation of AFP plasma levels; 
• Evaluation of tumoral and other clinical prognostic features at baseline; 
• Assessment of selected molecular alterations in circulating free DNA (cfDNA) at 
baseline. 
 
 
 
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5. TRIAL DESIGN AND DESIGN RATIONALE 
This is a Phase I/II, open-label, non-randomized, multicenter study to explore safety, 
tolerability and antitumor activity of NMS-01940153E as single agent in adult patients with 
unresectable HCC previously treated with systemic therapy. 
An independent Data Safety Monitoring Board (DSMB) will provide study oversight through 
periodic safety evaluations and make recommendations on study progress in the transition 
from Phase I to Phase II and at the planned interim analysis for the futility of Phase II. 
The Phase I portion is designed as a dose-escalation study in sequential cohorts of patients 
aimed to obtain the MTD that is defined based on the DLTs observed in the first cycle of 
treatment. The selection of the starting dose and the dose escalation scheme is based on the 
safety information gained in the FIH study (EudraCT 2014-002023-10) and in consideration 
of the possible different tolerability in patients with compromised liver. 
Once the MTD is identified and the safety profile of NMS-01940153E has been reviewed by 
the Investigators, the Sponsor and the independent DSMB and is considered adequate based 
on the entire Phase I data available, the Phase II portion of the study started.  
The Phase II portion is designed as a two-stage study with an interim analysis for futility and 
stopping criteria for unacceptable toxicity to assess the antitumor activity of NMS-01940153E 
in adult patients with unresectable HCC previously treated with systemic therapy measured 
as objective response rate. 
5.1. Treatment administration: 
NMS-01940153E is supplied as labeled type I glass vials containing 30 mg/vial of powder for 
solution for infusion. Each labeled vial (primary packaging) is packaged in a labeled single 
small carton (secondary packaging). 
Patients will receive treatment with NMS-01940153E administered as intravenous (IV) 
infusion for 3 consecutive weeks on days 1, 8, 15 followed by 1 week of rest, in a 28-day 
cycle. The duration of infusion will be dependent on the total dose to be administered: 
• 1 hour infusion if ≤255 mg are administered 
• 1 hour 30 minutes infusion if >255 mg but <375 mg are administered 
Within one cycle, in case the patient cannot be retreated on the day foreseen because of 
toxicity, the dose will be skipped and the patient will be retreated at the next foreseen time-
point. 
Dose reduction/omission is foreseen based on toxicities observed (see Section 9.2.3.1). 
Patients that cannot be retreated for any reason within 1 week from day 28 (up to day 35) will 
go off-treatment, unless the investigator believes treatment continuation is in the patient’s best 
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interest. In this case a maximum delay of 2 weeks (up to day 42) will be allowed. Otherwise 
patients may continue on investigational drug until disease progression, unacceptable toxicity, 
withdrawal of consent by the patient or other discontinuation criteria described in the protocol 
are met. 
Phase I Dose Escalation 
The safety profile of NMS-01940153E administered IV on days 1, 8, 15 every 4 weeks has 
been characterized in the FIH, dose escalation study, conducted in adult patients with 
advanced/metastatic solid tumors up to the dose of 135 mg/m2/week. This dose was not 
defined as MTD in study 2014-002023-10 (EudraCT), since only one patient experienced 
DLT (Grade 3 fatigue) out of 6 evaluable patients. 
Considering the possible different tolerability in patients with compromised liver, the 
proposed starting dose for the Phase I portion of the study is 100 mg/m2/week, which is an 
intermediate dose level between the highest (135 mg/m2/week) and the next lower dose level 
(67.5 mg/m2/week) tested in the FIH study [16]. According to the observed safety profile, 
dose increments of 25-35% will be applied to the proposed starting dose, until the MTD is 
reached. In presence of unacceptable toxicity observed at 100 mg/m2/week, a lower dose level 
by 25-35% may be tested. 
Patients experiencing DLT during the DLT window can be retreated according to the time 
delay and dose modification schema. 
No intra-patient dose escalation will be allowed. 
Phase II 
In the Phase II portion of the study, patients will be treated at the RP2D defined in the Phase I 
portion as starting dose. 
5.2. Phase I Dose Escalation 
A conventional 3+3 study design with inter-individual dose-escalations will be adopted. 
Patients will be allocated to sequential cohorts of progressively higher dose levels of NMS-
01940153E based on the presence of Dose Limiting Toxicities (DLT). 
At each dose level, a minimum of 3 patients will be included. 
If 0/3 patients experiences first cycle DLT, the next cohort will start one dose level higher. 
If 1/3 patients experiences first cycle DLT, up to three more patients will receive the study 
medication at the same dose level; if 1/6 patients experiences first cycle DLT the next cohort 
will start one dose level higher. 
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If ≥2/3 or ≥2/6 patients experience DLTs in the first cycle of treatment, the MTD is considered 
to have been exceeded. Three more patients will be entered at the previous dose level (if only 
3 patients were previously treated at that prior dose) or, in case the MTD is exceeded at the 
starting dose level, six patients will be entered to a lower dose level. 
Only one dose level will be open for enrollment at any time. 
The first patient enrolled on a dose level should be observed for DLT for at least 2 weeks 
before entering any other patient at that dose level. 
In absence of 1st cycle DLT in the first patient, the third patient can be enrolled at any time. 
In presence of 1st cycle DLT in the first patient, the third patient can be enrolled only after the 
second patient has completed the first cycle without DLT. 
In case a cohort needs to be expanded to more than 3 patients, the additional patients can be 
enrolled simultaneously. 
All patients must be observed for one cycle before subsequent patients are enrolled at the next 
higher dose level. If a patient fails to receive at least 66% of the first cycle of treatment, for 
reasons other than treatment-related toxicities, an additional patient must be enrolled at the 
same dose level. 
After the completion of each cohort, available safety and pharmacokinetic (PK) data will be 
reviewed and new dose levels were decided jointly by the Investigators and the Sponsor. 
5.2.1. Definition of DLTs 
For this protocol, a DLT will be defined as any of the following events for which the 
relationship to NMS-01940153E cannot be definitely excluded. Toxicities are to be graded 
according to the NCI CTCAE version 5.0 [21]. 
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Table 1. DLT criteria 
Hematological Toxicity 
Neutropenia 
Grade 4 lasting >7 days or 
Grade 4 of any duration associated with Grade ≥2 
infection 
Febrile neutropenia 
ANC <1000/mm3 and a single temperature of >38.3 
degrees C or a sustained temperature of ≥38 degrees 
C for more than one hour. 
Thrombocytopenia 
Grade 3 associated with any grade bleeding or 
Grade 4  
Anaemia 
Grade ≥4 
Non-Hematological Toxicity 
Nausea, vomiting or diarrhea 
Grade ≥3 despite optimal treatment 
Signs of potential severe drug-induced liver injury 
as assessed according to Hy's law 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 ULN and total bilirubin 
>2 ULN in the absence of cholestasis (alkaline 
phosphatase [ALP] <2 ULN) and no other reason can 
be identified. 
Any other non-hematological toxicities;  
Grade ≥ 3 toxicities unless clear alternate etiology is 
documented by the investigator and except: 
- asymptomatic Grade 3 electrolyte  changes that can 
be successfully supplemented (e.g., hypokalemia) 
and resolve/recover to baseline within 72 hours 
- Grade 3 fatigue that improves to ≤ Grade 2 in no 
more than 5 days 
- alopecia 
Other significant toxicity 
Failure to complete the first cycle of treatment with 
at least 66% of the planned total dose due to 
toxicity possibly related to the study medication 
- 
Failure to start Cycle 2 for more than 1 week (day 
36 or later) due to persistent Grade ≥ 2 toxicities 
possibly related to the study medication, excluding 
fatigue 
- 
Any toxicity that is possibly related to the study 
medication and requires the withdrawal of the 
patient 
from the study during the DLT observation period 
- 
Any on-study death not clearly due to the 
underlying disease or extraneous causes 
- 
5.2.2. DLT window 
The DLT window is defined as the time interval between the day of the first dose 
administration in Cycle 1 and the day of the first dose administration in Cycle 2 which is 
expected to be 28 days or up to 35 days in case of dose delay. For patients who do not receive 
Cycle 2, 35 days will be the time interval considered for the evaluation of DLT, unless no 
toxicities are observed, or recovery of toxicities occurs earlier or unless the patient has disease 
progression and/or starts a new anti-cancer therapy earlier. 
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5.2.3. Patient replacement 
During the first cycle of the dose-escalation phase, patients who meet any of the following 
criteria will not permit the DLT evaluation and therefore will be replaced: 
• Did not receive at least 66% of cycle study drug, unless treatment was stopped due to 
toxicity possibly related to the study medication; 
• Did not undergo DLT assessment in the DLT window. 
5.2.4. Definition of MTD and RP2D 
The MTD is the dose level at which 0/6 or 1/6 patients experience DLT in the first cycle of 
treatment with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. 
Effectively, the MTD is the highest dose associated with first cycle DLT in < 33% of patients. 
This dose or an inferior one may be the dose recommended for further Phase II investigation 
(RP2D). 
5.3. Phase II 
The Phase I part of the trial ended on May 30th, 2022 with the declaration of an RP2D of 100 
mg/m2/week, and the study has already received a unanimous recommendation from an 
independent Data Safety Monitoring Board (DSMB) to continue the trial, moving to Phase II 
study. 
The RP2D of 100 mg/m2/week, 3 of 4 weekly schedule, is justified based on safety, efficacy 
and pharmacokinetic considerations.  The trend of dose-related neutropenia as the major 
safety feature points to the 100 mg/m2/week level as more tractable relative to 135 mg/m2 
(refer to full safety summaries in the IB).  In terms of anti-tumor activity, the fact that, out of 
6 evaluable, one confirmed RECIST partial response (despite one missed dose during the first 
two cycles) plus one highly prolonged stable disease were observed at 100 mg/m2 as well as, 
out of 4 evaluable, 2 patients with substantial AFP reduction were observed points to 
reasonable activity at this dose level.  Furthermore, pharmacokinetics at the 100 mg/m2 dose 
level are in a meaningful range relative a continuous mouse tumor stabilization model 
predicting 0.2 uM average concentration threshold relative to the 100 mg/m2 mean Cmax in 
HCC patients which is 7 fold higher at 1.35 uM and with AUC just slightly below the mouse 
threshold, 32.5 uM*h versus 35.  Refer to IB for full PK descriptions.  RECIST response and 
AFP reductions were observed at the 135 mg/m2/w level and PK was slightly higher but 
overall the anti-tumor pattern at 135 was similar to 100 mg/m2.  Therefore, overall, the 100 
mg/m2 level is justifiable as the RP2D. 
In the Phase II portion, patients will receive the RP2D defined in the Phase I portion of the 
study as starting dose.  
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As soon as signs of toxicity are observed requiring a dose de-escalation, the dose will be 
decreased as described in Section 9.2.3.1, Table 6). A maximum of two dose decreases will 
be allowed, otherwise patient will have to be withdrawn from the study. 
Patients will be enrolled in continuous, and continuously evaluated for endpoints, with a 
futility analysis and stopping criteria for unacceptable toxicity performed as described in 
Section 12. The enrollment will be stopped in the event of futility as described in Section 12, 
with no more than 20 subjects treated overall until non-futility can be declared, if appropriate.  
In any case, the Sponsor may stop or pause enrollments any time during the study based on 
safety, efficacy or strategic reasons. 
 
 
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6. SUBJECT SELECTION 
This clinical trial can fulfill its objectives only if appropriate subjects are enrolled. The 
following eligibility criteria are designed to select subjects for whom protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
6.1. Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:  
1. Histological, cytological or radiological diagnosis of HCC, according to the American 
Association for the Study of Liver Diseases (AASLD) / European Association for the 
Study of the Liver (EASL) criteria, in subjects that are refractory or not able to tolerate 
the standard therapy, or subjects for whom the standard therapy is not considered 
appropriate by the physician. 
2. The subject has disease that is not amenable to a curative treatment approach (e.g., 
transplant, surgery, radiofrequency ablation) and unsuitable for or refractory to 
locoregional treatments (e.g., TACE). 
3. At least one uni-dimensional measurable lesion by CT or MRI according to RECIST 1.1 
which is either not previously treated by local therapy or, if treated, it has clearly 
progressed before the subject is recruited. 
4. Phase I only: subjects must have disease relapsed or refractory to the standard of care 
treatment not exceeding 3 lines of prior systemic treatment. Subjects intolerant to previous 
treatment with TKIs are eligible.  
Phase II: subjects must have disease relapsed or refractory to the standard of care treatment 
including an immunocheckpoint inhibitor as first line and at least a tyrosine kinase 
inhibitor, not exceeding 3 lines of prior systemic treatment. 
 
A minimum of 14 days of treatment with prior TKI would be required to qualify as line 
of therapy; 
5. Child-Pugh score ≤ 6 (class A, see Appendix 2). 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
7. Age 18 years old on day of consent. 
8. No history of liver transplantation or not listed for high urgent transplantation. 
 
 
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9. Required laboratory data:  
Absolute neutrophil count (ANC) 
 1,500/mm3 (> 1.5 x 109/L) 
Platelets 
 60,000/mm3 ( 60.0 x 109/L) 
Hemoglobin* 
 10.0 g/dL 
Albumin 
 3.0 g/dL ( 30 g/L) 
Total serum bilirubin 
 1.5 x ULN and no more than 2 mg/dl, unless 
abnormality considered due to Gilbert’s syndrome 
Creatinine clearance** 
> 60 mL/min  
ALT/AST  
 5 x ULN 
INR 
 1.5 
*Transfusions of red blood cells or other hemocomponents not allowed within 72 h before treatment start. 
**Calculated using the Cockroft-Gault equation (mL/min): (140 – age) x weight (kg) / (serum creatinine 
[mg/dL]× 72) for males. (For females multiply by 0.85) 
10. In case of active hepatitis B (HBV) or chronic HIV infection the patient should receive 
antiviral therapy per local standard of care. 
11. Patients must use effective contraception or abstinence. Female subjects must be 
surgically sterile or, if subjects of childbearing potential, must agree to use effective 
contraception (see Appendix 6) or abstinence during the period of therapy and in the 
following 180 days after discontinuation of study treatment. Male subjects must be 
surgically sterile or must agree to use effective contraception or abstinence during the 
period of therapy and in the following 90 days after discontinuation of study treatment. 
12. With the exception of alopecia, resolution of all acute toxic effects of any prior systemic 
therapy, surgery or radiotherapy to NCI CTC (Version 5.0) Grade ≤1 or to the baseline 
laboratory values as defined in Inclusion Criterion Number 9. 
13. Able and willing to comply with scheduled visits, therapy plans, and laboratory tests 
required in this protocol. 
14. Signed and dated IEC-approved Informed Consent Form indicating that the subject is 
aware of the neoplastic nature of his/her disease and has been informed of the procedures 
to be followed, the investigational nature of the therapy, potential benefits, side effects, 
discomforts, risks and alternative treatments. 
6.2. Subject Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrollment: 
1. Known fibrolamellar HCC or mixed hepato-cholangiocarcinoma. 
2. Subjects with untreated or incompletely treated varices with bleeding or high risk for 
bleeding are excluded with the following clarification: subjects with history of prior 
variceal bleeding must have been treated with adequate endoscopic therapy without any 
evidence of recurrent bleeding for at least 6 months prior to study entry and must be stable 
on optimal medical management (e.g. non-selective beta blocker, proton pump inhibitor) 
at study entry. 
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3. Subjects with QTcF interval ≥480 milliseconds or with risk factors for torsade de pointes 
(e.g., heart failure, uncontrolled hypokalemia, family history of long QT syndrome) or 
receiving treatment with concomitant medications known to prolong the QT/QTc interval 
that cannot be replaced with another treatment. 
4. Ascites defined as CTCAE Grade ≥2. Subjects who have been on a stable medication 
regimen for at least 2 months to manage ascites are eligible if they show ascites Grade < 
2. Subjects with clinically undetectable ascites who are Child A with detectable ascites at 
CT/MRI are eligible. 
5. Uncontrolled high blood pressure (systolic blood pressure, SBP >150 mmHg and/or 
diastolic blood pressure, DBP >95 mmHg, despite optimal treatment, on at least 2 out of 
3 determinations repeated at 30 minutes interval and done in case that the first one meets 
the criterion for exclusion). 
6. Direct-Acting Antivirals (DAA) at the time of treatment start; previous HCV treatment 
with DAAs is allowed. 
7. Clinical evidence of hepatic encephalopathy. 
8. Known brain metastases or evidence of leptomeningeal disease. 
9. Known history of allergic reactions to polysorbate 80. 
10. Any of the following in the past 6 months: myocardial infarction, uncontrolled cardiac 
arrhythmia, unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary 
embolism, deep vein thrombosis (except chronic/stable portal vein thrombosis). 
11. Major surgery, other than diagnostic surgery, within 4 weeks before treatment start. 
12. Any anticancer agent within 4 weeks or, in absence of toxicity, 5 half-lives (within 6 
weeks for nitrosureas, mitomycin C and liposomal doxorubicin) before treatment start. 
13. Radiation therapy within 4 weeks or radionuclide treatment (e.g., I-131 or Y-90) within 6 
weeks before treatment start. 
14. Untreated uncontrolled bacterial, viral, or fungal infections including acute HIV infection 
or acquired immunodeficiency syndrome (AIDS), untreated uncontrolled HBV, untreated 
uncontrolled HCV, untreated uncontrolled concomitant HBV and HCV; patients who are 
seropositive following HBV vaccine are eligible. 
15. Subjects under treatment with therapeutic dose of anticoagulants (e.g., warfarin or 
warfarin-related agents, low-molecular weight heparin, or similar agent such as anti Xa 
and anti-thrombin agents) or antiplatelet agents (e.g. clopidogrel) or with coagulation 
disorders. Aspirin at dose up to 100 mg is permitted. Prophylaxis with anticoagulants is 
allowed to meet the INR value range as cited in inclusion criterion 9. 
16. Uncontrolled diabetes mellitus. 
17. Pregnant or breast-feeding women. 
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18. Known second malignancy that is progressing or requiring active treatment. Exceptions 
include adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of 
the cervix uteri. 
19. Current enrollment or participation in another interventional clinical trial. 
20. Clinically significant respiratory or metabolic diseases uncontrolled by medication. 
21. Subjects with active alcohol and/or substances abuse. 
22. Any known organ dysfunction, serious illness, acute or chronic medical or psychiatric 
condition, or laboratory abnormality which, in the Investigator’s opinion, may increase 
the risk associated/interfere with study participation, or with the interpretation of the 
results. 
23. Subjects who, within 7 days prior to the first NMS-01940153E intake, are receiving or 
received strong inducers of FMO1and FMO3. 
24. Subjects who are receiving sensitive CYP3A4 substrates, CYP3A4 and BCRP substrates 
with narrow therapeutic index (NTI). 
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7. SCHEDULE OF EVENTS 
 
Table 2. Phase I Schedule of Events 
Protocol activities 
and forms to be completed 
Screening 
(day) 
Cycle 1 (day) 
Cycle >1 (day) 
Last cycle 
Off Treatment 
assessments 25 
<28 
<7 
1 
2 
3 
4 
8 
15 
16 
17 
18 
22 
1 
8 
15 
22 
28 
EoT24 
28D FU 
Bi-mth FU 
Informed Consent 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical/oncologic history 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 3 
 
X 
X* 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 4 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Temperature 5 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Blood pressure and heart rate 6 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
 
 
X 
X 
 
Gastro-esophageal endoscopy 7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 8 
 
X 
As medically indicated 
As medically indicated 
X 
 
 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 9  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Serology 10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 11 
 
X 
X* 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Blood chemistry 12 
 
X 
X* 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Coagulation 13 
 
X 
X* 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
AFP 14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Urinalysis 15 
 
X 
As medically indicated 
As medically indicated 
X 
 
 
Other clinical assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 16 
X 
X 
X 
X 
X 
X 
 
Adverse Events 17 
X 
X 
X 
X 
X 
X 
 
Study treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NMS-01940153E infusion 19 
 
 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Disease assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor imaging 20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Survival follow up 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Investigational assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood sample 22 
 
 
X° 
X° 
X° 
X° 
X° 
X° 
X° 
X° 
X° 
X° 
X° 
X° 
X° 
 
 
 
 
 
PK urine sample 23 
 
 
X° 
 
X° 
 
 
 
 
 
 
 
 
 
 
See Footnotes for Schedule of Events on following page 
 
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Footnotes for Phase I Schedule of events 
1. Informed consent: to be obtained before the starting of any trial related procedure; it may occur also before the 28-day screening period. After signature, a subject Screening number is assigned centrally. 
2. Relevant medical/oncologic history: to be assessed at screening, within 7 days from treatment start. Medical history includes history of relevant medical conditions and concomitant illnesses either 
present (active or controlled) or resolved. Oncologic history includes information on initial diagnosis, prior regimens and best response to prior regimens. 
3. ECOG PS: to be recorded at screening, within 7 days from treatment start; on day 1 of each treatment cycle (before treatment administration); at end of treatment (EoT) and at 28-days follow up. 
4. Weight (kilograms): to be recorded at screening, within 7 days from treatment start, and on day 1 of each treatment cycle (before treatment administration). 
5. Temperature (Celsius degree): to be recorded at screening, within 7 days from treatment start, and on days 1, 8, 15 of each treatment cycle (before treatment administration). 
6. Blood pressure and heart rate (supine): to be recorded at screening, within 7 days from treatment start; on days 1, 8, 15 before the treatment start and within 30 minutes after the end of infusion; at EoT 
and 28-days follow up. At each determination, if SBP > 150 mmHg and/or DBP > 95 mmHg is registered, repeat determinations two more times at 30 minutes interval. 
7. Gastro-esophageal endoscopy: to be performed to all patients with known history for gastro-esophageal varices. For these patients, the assessment is mandatory at screening, within 7 days from 
treatment start, unless an endoscopy is available within 3 months before the treatment start. 
8. 12-lead ECG: to be performed to determine QT interval using Fridericia standard (QTcF) at screening, within 7 days from treatment start, and at EoT visit. To be repeated at any time it is medically 
indicated. 
9. Pregnancy test (serum/urine): for women of childbearing potential only, to be performed at screening, within 72 hours from treatment start and at EoT visit. 
10. Serology: in case of positive HBV anamnesis, includes HBV DNA; in case of positive HCV anamnesis, includes HCV RNA; in case of HBV unknown anamnesis, includes HbsAg, HbeAg, HbcAg, Anti-HBc-IgM; 
in case of HCV unknown anamnesis, includes liver function test as by local standards and HCV Ab. Anti-HIV test. To be performed at screening, within 7 days from treatment start.  
11. Hematology: includes hemoglobin (Hb), red blood cells (RBC), platelet (PLT) and white blood cells (WBC) with differential count (neutrophils, lymphocytes, monocytes, eosinophils and basophils). To be 
performed at screening, within 7 days from treatment start; from cycle 1 to cycle 3, on days 1, 8, 15, 22; from cycle 4 onward, on days 1, 8, 15; at EoT and 28-days follow up. A time window of -1 day is 
allowed; on days of treatment administration, sampling should be performed and results should be available before the start of NMS-01940153E infusion. In case of cycle delay due to toxicity and/or if 
clinically indicated, additional assessments should be done as per medical judgment. 
12. Blood chemistry: includes glucose, electrolytes (Na, K, Ca, P, magnesium), urea, serum creatinine, creatinine clearance (calculated with Cockroft-Gault equation), total protein, albumin, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), gamma-glutamil transferase (-GT), total bilirubin, unconjugated bilirubin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH). To 
be performed at screening, within 7 days from treatment start; from cycle 1 to cycle 3, on days 1, 8, 15, 22; from cycle 4 onward, on days 1, 8, 15; at EoT and 28-days follow up. A time window of -1 day is 
allowed; on days of treatment administration, sampling should be done and results should be available before the start of NMS-01940153E infusion. In case of cycle delay due to toxicity and/or clinically 
indicated, additional assessments should be done as per medical judgment. 
13. Coagulation: includes international normalized ratio (INR) of prothrombin. To be performed at screening, within 7 days from treatment start; from cycle 1 to cycle 3, on days 1, 8, 15, 22; from cycle 4 
onward, on days 1, 8, 15; at EoT and 28-days follow up. A time window of -1 day is allowed; on days of treatment administration, sampling should be done and results should be available before the start of 
NMS-01940153E infusion. In case of cycle delay due to toxicity and/or clinically indicated, additional assessments should be done as per medical judgment. 
14. AFP: to be performed at screening, within 7 days from treatment start, at the end of even cycles at disease evaluation and at EoT. A time window of -2/+5 days is allowed. 
15. Urinalysis: includes pH, glucose, protein and blood. To be performed at screening, within 7 days from treatment start, and at EoT. To be repeated as medically indicated. 
16. Concomitant medications: includes all treatment, supportive care taken (started or completed), transfusion, procedures and hospitalization up to 28 days before treatment start. Once the patient has 
ended the study treatment, concomitant medications should be recorded for 28 days (in case, up to 35 days) after the last on-study treatment administration or until all study drug-related toxicities have 
resolved, whichever comes first, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the new treatment is started. 
17. Adverse events: to be documented at each scheduled visit since patient signs the Informed Consent until 28 days after the last treatment administration, or until all serious or study drug-related toxicities 
have resolved or are determined to be “chronic” or “stable”, whichever comes first, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the new treatment 
is started. 
18. Enrolment: the investigator request of subject enrolment is the guarantee that all the eligibility criteria are met; Enrolment number and dose level are assigned centrally. It is recommended to start the 
treatment within 1-4 days from patient enrolment. 
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19. NMS-01940153E infusion: patients will receive treatment with NMS-01940153E administered as IV infusion for 3 consecutive weeks on days 1, 8, 15 followed by 1 week of rest, in a 28-day cycle. The 
duration of infusion will be dependent on the total dose to be administered: 1 hour infusion if <255 mg are administered; 1 hour 30 minutes infusion if >255 mg but <375 mg are administered. Within one 
cycle, in case the patient cannot be retreated on the day foreseen because of toxicity, the dose will be skipped and the patient will be retreated at the next foreseen time-point. Dose reduction/omission is 
foreseen based on toxicities observed. Patients that cannot be retreated, for any reason, within 1 week from day 28 will go off-treatment, unless the investigator believes treatment continuation is in the 
patient best interest. In this case a maximum delay of 2 weeks (up to day 42 from cycle start) will be allowed. Otherwise patients may continue on investigational drug until a withdrawal criterion is met. 
20. Tumor imaging: to be performed at screening, within 28 days from treatment start (in case a tumor imaging is already available in the specified time window, it has not to be repeated); at the end of 
even months (even cycles) of treatment and at EoT. The EoT assessment is to be performed only if it was not performed in the previous 4 weeks. In patients withdrawn for reasons other than progressive 
disease (PD), during follow up, tumor assessment should be performed every 2 months, until PD or until a new antitumor therapy starts. On treatment, a time window of -2/+5 days is allowed. Patients with 
responding tumors (complete or partial response) must have response confirmed by CT scan at least 4 weeks after the 1st documentation of response. The same method of assessment and technique should 
be used to characterize and follow the same lesion at screening, during treatment and at EoT. CT scan is the desirable method for lesion measurement (see Section 11.3.1). 
21. Survival follow up: post-treatment survival status, including additional information (e.g. new anticancer therapy), will be collected at the 28-days follow up visit and thereafter every 2 months from last 
treatment administration until death. Telephone contacts are acceptable for these assessments. 
22. PK blood sample: during the Phase I, blood sampling for PK is to be performed at cycles 1 and 2 only (refer to Table 3 for details). During the Phase II, a sparse sampling procedure will be adopted. 
23. PK urine sample: urine collection for PK is to be performed at cycle 1, only, on days 1, 15. Urine will be collected before the treatment administration and in four different portions between 0-6h, 6-24h, 
24-48h, 48-72h from the start of study drug administration. 
24. End of Treatment (EoT): visit to be performed within 7 days from the decision of discontinuing the study drug. 
25. Off treatment assessments: 28 days, and no more than 35 days, after discontinuation of study treatment patients will return for the following assessments: ECOG PS, blood pressure and heart rate, 
hematology, blood chemistry, coagulation, concomitant medications, adverse events and survival follow up. Further follow up contacts will be scheduled every 2 months from last treatment administration, 
until death, to assess the survival status, including possible additional information. 
28 day follow up for laboratory abnormalities: in case hematology, blood chemistry, coagulation, study drug-related and clinically significant abnormalities persist beyond the 28-days follow up assessment, 
they should be followed until they resolve or the Investigator assess them as chronic or stable, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the 
new treatment is started. 
28 days follow up for adverse events: the AEs reporting period ends 28 days after the last study treatment administration. The following events should be followed after the end of the reporting period: 
serious adverse events (SAEs) with outcome “not recovered” or “unknown” and study drug-related AEs with outcome “not recovered” or “unknown”. They have to be followed until they resolve or the 
Investigator assess them as chronic or stable, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the new treatment is started. 
* Cycle 1 Day 1 assessments: evaluations do not need to be repeated before study drug administration if they were performed at screening within 24 hours from treatment start. 
° refer to Table 3  
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Table 3. Investigational Assessments details for Phase I 
 
Cycle 1 (Day) 
Cycle 2 (Day) 
D1, D15 
D2, D16 
D3, D17 
D4, D18 
D8, D22 
D1, D8, D15 
Timing related to 
EoI (hour) 
Pre 
- 
0.0§ 
0.15 
0.30 
1.0 
2.0 
4.0 
6.0 
7.0 
8.0 
24.0 
48.0 
72.0 
168.0 
Pre-dose 
Study drug infusion 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samplea 
X 
 
X§ 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Blood pressureb 
X€ 
 
 
 
X€ 
 
 
 
 
 
 
 
 
 
X+€# 
X+€ 
 
a. PK blood samples: all patients enrolled in the Phase I portion of the study will undergo blood draws for PK analysis (central laboratory). 
Phase I Dose-Escalation  
Cycle 1: 
Day 1: before the start of infusion, 5 minutes before the end of infusion (0.0§), 15 minutes, 30 minutes, 1h, 2h, 4h, 6h, 8h after the end of study drug administration 
Day 2: 24h after the end of study drug administration 
Day 3: 48h after the end of study drug administration 
Day 4: 72h after the end of study drug administration 
Day 8: before the start of infusion 
Day 15: before the start of infusion, 5 minutes before the end of infusion (0.0§), 15 minutes, 30 minutes, 1h, 2h, 4h, 6h, 8h after the end of study drug administration 
Day 16: 24h after the end of study drug administration 
Day 17: 48h after the end of study drug administration 
Day 18: 72h after the end of study drug administration 
Day 22: 168h after the end of study drug administration 
Cycle 2:  
Day 1: before the start of infusion 
Day 8: before the start of infusion 
Day 15: before the start of infusion 
Phase II 
During the Phase II portion of the study, a sparse sampling procedure will be adopted. 
 
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b. Blood Pressure 
Phase I Dose-Escalation  
Cycle 1: 
Day 1: before the start of infusion and within 30 minutes after the end of study drug administration; before the blood sample for PK is taken. 
Day 8: before the start of infusion and within 30 minutes after the end of study drug administration; before the blood sample for PK is taken. 
Day 15: before the start of infusion and within 30 minutes after the end of study drug administration; before the blood sample for PK is taken. 
Cycle 2:  
Day 1: before the start of infusion and within 30 minutes after the end of study drug administration; before the blood sample for PK is taken. 
Day 8: before the start of infusion and within 30 minutes after the end of study drug administration; before the blood sample for PK is taken. 
Day 15: before the start of infusion and within 30 minutes after the end of study drug administration; before the blood sample for PK is taken. 
 
+ before the treatment start and within 30 minutes after the end of infusion 
§ 5 minutes before the end of infusion (EoI) 
# on D8 only 
€ before the blood sample is taken 
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Table 4. Phase II Schedule of Events 
Protocol activities 
and forms to be completed 
Screening 
Cycle 1 (day) 
Cycle > 1 (day) 
Last cycle 
Off treatment 
assessments 26 
< 28 
< 7 
1 
8 
15 
22 
1 
8 
15 
28 
EoT 25 
28D FU 
Bi- mth FU 
Informed Consent 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical/oncologic history 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination and ECOG PS 3 
 
X 
X* 
 
 
 
X 
 
 
 
X 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 4 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Temperature 5 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Blood pressure and heart rate 6 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Gastro-esophageal endoscopy 7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 8 
 
X 
X 
 
X 
 
As medically indicated 
X 
 
 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 9 
 
X 
X* 
 
 
 
X 
 
 
 
X 
 
 
Serology 10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 11 
 
X 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Blood chemistry 12 
 
X 
X* 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Coagulation 13 
 
X 
X* 
X 
X 
X 
X 
 
X 
 
X 
X 
 
AFP 14 
 
X 
 
 
 
 
 
 
 
X• 
X 
 
 
Urinalysis 15 
 
X 
As medically indicated 
As medically indicated 
X 
 
 
Other clinical assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 16 
X 
X 
X 
X 
X 
X 
 
Adverse events 17 
X 
X 
X 
X 
X 
X 
 
Study treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
NMS-01940153E infusion 19 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Disease assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor imaging 20 
X 
 
 
 
 
 
 
 
 
X• 
X 
 
X 
BCLC and TNM staging21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Survival follow up 22 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Investigational assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers sampling23 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PK blood sample 24 
 
 
X° 
X° 
X° 
X° 
X° 
 
X° 
X° 
 
 
 
See Footnotes for Schedule of Events on following page 
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Footnotes for Phase II Schedule of events 
1. Informed consent: to be obtained before the starting of any trial related procedure; it may occur also before the 28-days screening period. After signature, a subject Screening number is assigned centrally. 
2. Relevant medical/oncologic history: to be assessed at screening, within 7 days from treatment start. Medical history includes history of relevant medical conditions and concomitant illnesses either 
present (active or controlled) or resolved. Oncologic history includes information on initial diagnosis, prior regimens and best response to prior regimens. 
3. Physical examination and ECOG PS: to be recorded at screening, within 7 days from treatment start; on day 1 of each treatment cycle (before treatment administration); at EoT and at 28-days follow up. 
4. Weight (kilograms): to be recorded at screening, within 7 days from treatment start, and on day 1 of each treatment cycle (before treatment administration). 
5. Temperature (Celsius degree): to be recorded at screening, within 7 days from treatment start, and on days 1, 8, 15 of each treatment cycle (before treatment administration). 
6. Blood pressure and heart rate: to be recorded at screening, within 7 days from treatment start; on days 1, 8, 15 before the treatment start and within 30 minutes after the end of infusion; at EoT and 28-
days follow up. At each determination, if SBP > 150 mmHg and/or DBP > 95 mmHg is registered, repeat determinations two more times at 30 minutes interval. 
7. Gastro-esophageal endoscopy: to be performed to all patients with known history of gastro-esophageal varices. For these patients the assessment is mandatory, at screening within 7 days from treatment 
start, unless an endoscopy is available within 3 months before the treatment start. For all other patients the assessment is not required, granted that an endoscopy is available within 24 months before the 
treatment start, or PI would justify the absence of clinical need for this assessment; 
8. 12-lead ECG (12-lead, in triplicate, includes qualitative and quantitative assessment): to be performed to determine QT interval using Fridericia standard (QTcF) at screening, within 7 days from 
treatment start, at cycle 1 day 1 (first dose) and at cycle 1 day 15 (dose 3) triplicate ECG will be collected prior to dosing (30 min before the start of infusion and at least 10 minutes after any blood drawn 
or intravenous access procedure) and at peak concentration, prior to and as close as possible to the PK timepoint planned 5 minutes before the end of infusion (e.g. ≤ 10 minutes),, and at EoT visit. To be 
repeated at any time it is medically indicated. If the ECG assessment is not feasible on cycle 1 day 1 or cycle 1 day 15, a different timing or other solutions should be discussed with Sponsor. Additional 
assessments to be performed if clinically indicated. At each time point, three consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QT interval using 
Fridericia standard (QTcF). The following parameters will be collected: synus rithm, heart rate, RR interval, PR interval, QRS interval, QT interval and QTcF interval. For all patients enrolled in the study, the 
Sponsor may request the ECG tracing and reports collected during the study be submitted to a third-party for retrospective independent review of the ECGs reading and interpretation.  
9. Pregnancy test (serum/urine): for women of childbearing potential only, to be performed at screening, within 72 hours from treatment start, on day 1 of each treatment cycle (before treatment 
administration) and at EoT visit. 
10. Serology: in case of positive HBV anamnesis, includes HBV DNA; in case of positive HCV anamnesis, includes HCV RNA; in case of HBV unknown anamnesis, includes HbsAg, HbeAg, HbcAg, Anti-HBc-IgM; 
in case of HCV unknown anamnesis, includes liver function test as by local standards and HCV Ab. Anti-HIV test. To be performed at screening, within 7 days from treatment start.  
11. Hematology: includes hemoglobin (Hb), red blood cells (RBC), platelet (PLT) and white blood cells (WBC) with differential count (neutrophils, lymphocytes, monocytes, eosinophils and basophils). To be 
performed at screening, within 7 days from treatment start; on cycle 1, on days 1, 8, 15, 22; from cycle 2 onward, on days 1, 8, 15; at cycle 2, in case neutropenia Grade ≥2 is observed, repeat the hematological 
evaluation also at day 22; at EoT and 28-days follow up. A time window of -1 day is allowed; on days of treatment administration, sampling should be performed and results should be available before the 
start of NMS-01940153E infusion. In case of cycle delay due to toxicity and/or if clinically indicated, additional assessments should be done as per Investigator judgment. 
12. Blood chemistry: includes glucose, electrolytes (Na, K, Ca, P, magnesium), urea or BUN, serum creatinine, creatinine clearance (calculated with Cockroft-Gault equation), total protein, albumin, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), gamma-glutamil transferase (-GT), total bilirubin, unconjugated bilirubin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH). To 
be performed at screening, within 7 days from treatment start; on cycle 1, on days 1, 8, 15, 22; from cycle 2 onward, on days 1, 15; at EoT and 28-days follow up. A time window of -1 day is allowed; on days 
of treatment administration, sampling should be done and results should be available before the start of NMS-01940153E infusion. In case of cycle delay due to toxicity and/or clinically indicated, additional 
assessments should be done as per Investigator judgment. 
13. Coagulation: includes international normalized ratio (INR) of prothrombin. To be performed at screening, within 7 days from treatment start; on cycle 1, on days 1, 8, 15, 22; from cycle 2 onward, on 
days 1, 15; at EoT and 28-days follow up. A time window of -1 day is allowed; on days of treatment administration, sampling should be done and results should be available before the start of NMS-01940153E 
infusion. In case of cycle delay due to toxicity and/or clinically indicated, additional assessments should be done as per Investigator judgment. 
14. AFP: to be performed at screening, within 7 days from treatment start; at the end of even cycles and at EoT. A time window of -2/+5 days is allowed. 
15. Urinalysis: includes pH, glucose, protein and blood. To be performed at screening, within 7 days from treatment start and at EoT. To be repeated as medically indicated. 
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16. Concomitant medications: includes all treatment, supportive care taken (started or completed), transfusion, procedures and hospitalization up to 28 days before treatment start. Once the patient has 
ended the study treatment, concomitant medications should be recorded for 28 days (in case, up to 35 days) after the last on-study treatment administration or until all study drug-related toxicities have 
resolved, whichever comes first, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the new treatment is started. 
17. Adverse events: to be documented at each scheduled visit since patient signs the Informed Consent until 28 days after the last treatment administration, or until all serious or study drug-related toxicities 
have resolved or are determined to be “chronic” or “stable”, whichever comes first, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the new treatment 
is started. 
18. Enrolment: the investigator request of subject enrolment is the guarantee that all the eligibility criteria are met; Enrolment number is assigned centrally. It is recommended to start the treatment within 
1-4 days from patient enrolment. 
19. NMS-01940153E infusion: patients will receive treatment with NMS-01940153E administered as IV infusion for 3 consecutive weeks on days 1, 8, 15 followed by 1 week of rest, in a 28-day cycle. The 
duration of infusion will be dependent on the total dose to be administered: 1 hour infusion if <255 mg are administered; 1 hour 30 minutes infusion if >255 mg but <375 mg are administered. Within one 
cycle, in case the patient cannot be retreated on the day foreseen because of toxicity, the dose will be skipped, and the patient will be retreated at the next foreseen time-point. Dose reduction/omission is 
foreseen based on toxicities observed. Patients that cannot be retreated, for any reason, within 1 week from day 28 will go off-treatment, unless the investigator believes treatment continuation is in the 
patient best interest. In this case a maximum delay of 2 weeks (up to day 42 from cycle start) will be allowed. Otherwise patients may continue on investigational drug until a withdrawal criterion is met. 
20. Tumor imaging: to be performed at screening, within 28 days from treatment start (in case a tumor imaging is already available in the specified time window, it has not to be repeated); at the end of 
even months (even cycles) of treatment and at EoT. The EoT assessment is to be performed only if it was not performed in the previous 4 weeks. In patients withdrawn for reasons other than progressive 
disease (PD), during follow up, tumor assessment should be performed every 2 months, until PD or until a new antitumor therapy starts. On treatment, a time window of -2/+5 days is allowed. Patients with 
responding tumors (complete or partial response) must have response confirmed by CT scan at least 4 weeks after the 1st documentation of response. The same method of assessment and technique should 
be used to characterize and follow the same lesion at screening, during treatment and at EoT. Ct scan is the desirable method for lesion measurement (see Section 11.3.1). 
21. BCLC and TNM Staging: TNM and BCLC staging will be requested at enrollment for all patients, including collection of clinical related additional info 
22. Survival follow up: post-treatment survival status, including additional information (e.g. new anticancer therapy), will be collected at the 28-days follow up visit and thereafter every 2 months from last 
treatment administration until death. Telephone contacts are acceptable for these assessments. 
23. Biomarkers sampling: peripheral blood samples will be collected at Enrollment (≤7 days before Cycle1 Day1) for analysis of selected molecular alterations in circulating free DNA (cfDNA) from plasma 
24. PK blood sample: during the Phase II, a sparse sampling procedure will be adopted; blood sampling for PK is to be performed at cycles 1, 2, 3 and 4 (refer to Table 5 for details). 
25. End of Treatment (EoT): visit to be performed within 7 days from the decision of discontinuing the study drug. 
26. Off treatment assessments: 28 days, and no more than 35 days, after discontinuation of study treatment patients will return for the following assessments: ECOG PS, blood pressure and heart rate, 
hematology, blood chemistry, coagulation, concomitant medications, adverse events and survival follow up. Further follow up contacts will be scheduled every 2 months from last treatment administration, 
until death, to assess the survival status, including possible additional information. 
28 day follow up for laboratory abnormalities: in case hematology, blood chemistry, coagulation, study drug-related and clinically significant abnormalities persist beyond the 28-days follow up assessment, 
they should be followed until they resolve or the Investigator assess them as chronic or stable, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the 
new treatment is started. 
28 days follow up for adverse events: the AEs reporting period ends 28 days after the last study treatment administration. The following events should be followed after the end of the reporting period: 
serious adverse events (SAEs) with outcome “not recovered” or “unknown” and study drug-related AEs with outcome “not recovered” or “unknown”. They have to be followed until they resolve or the 
Investigator assess them as chronic or stable, or until alternative anticancer therapy is initiated. In this case, the reporting period will end at the time the new treatment is started. 
* Cycle 1 Day 1 assessments: evaluations do not need to be repeated before study drug administration if they were performed at screening within 24 hours from treatment start. 
• only even cycles 
 
 
 
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Table 5. Investigational Assessments details for Phase II 
 
Cycle 1 (Days) 
Cycles 2 and 4 (Days) 
Cycle 3 (Days) 
 
D1 
D8 
D15 
D22 
D1 
D15 
D26 - 28 
D15 
Timing related 
to EoI (hour) 
0.0§ 
15min – 2h 
>2h – 6h 
Pre 
0.0§ 
Pre 
0.0§ 
15min – 2h 
>2h – 6h 
Any 
Pre 
Pre 
0.0§ 
15min – 2h 
>2h – 6h 
Any 
Pre 
0.0§ 
15min – 2h 
>2h – 6h 
PK blood 
samplec 
X 
XOd 
XEv 
XOd 
XEv 
X 
X 
XEv 
XOd 
X 
X 
X 
X 
XOd 
XEv 
X 
X 
X 
XEv 
XOd 
c. PK blood samples: all patients enrolled in the Phase II portion of the study will undergo blood draws for PK analysis (central laboratory) based on their enrollment number (odd or even), as detailed below. 
 
Odd patients (XOd) 
Cycle 1: 
Day 1: 5 minutes before the end of infusion (0.0§), from 15 minutes to 2h after the end of study drug administration 
Day 8: before the start of infusion (pre-dose) 
Day 15: before the start of infusion (pre-dose), 5 minutes before the end of infusion (0.0§), from >2h to 6h after the end of study drug administration 
Day 22: one sample, at any time 
Cycles 2 and 4:  
Day 1: before the start of infusion (pre-dose) 
Day 15: before the start of infusion (pre-dose), 5 minutes before the end of infusion (0.0§), from 15 minutes to 2h after the end of study drug administration 
One samples on day 26 or day 27 or day 28, at any time. 
Cycle 3: 
Day 15: before the start of infusion (pre-dose), 5 minutes before the end of infusion (0.0§), from >2h to 6h after the end of study drug administration 
 
Even patients (XEv) 
Cycle 1: 
Day 1: 5 minutes before the end of infusion (0.0§), from >2h to 6h after the end of study drug administration 
Day 8: 5 minutes before the end of infusion (0.0§) 
Day 15: before the start of infusion (pre-dose), 5 minutes before the end of infusion (0.0§), from 15 minutes to 2h after the end of study drug administration 
Day 22: one sample, at any time 
Cycles 2 and 4:  
Day 1: before the start of infusion (pre-dose) 
Day 15: before the start of infusion (pre-dose), 5 minutes before the end of infusion (0.0§), from >2h to 6h after the end of study drug administration 
One samples on day 26 or day 27 or day 28, at any time. 
Cycle 3: 
Day 15: before the start of infusion (pre-dose), 5 minutes before the end of infusion (0.0§), from 15 minutes to 2h after the end of study drug administration 
Note: blood pressure is to be taken on days 1, 8, 15 before the treatment start and within 30 minutes after the end of infusion, before the blood sample for PK is taken (if the case). 
 
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8. ENROLLMENT PROCEDURES 
Patients considered suitable will be informed about study and procedures, both verbally and 
by written information. Patients will be given all the time they need for reading information 
provided, discuss and question them and ask others’ opinion. Patients who will decide to 
participate in the study will sign and date the informed consent form (ICF) before starting any 
trial related procedures; concomitantly, the Investigator will also sign and date the form. 
After the signature of the ICF, a screening number will be centrally assigned to the patient, 
allowing the screening process for eligibility to begin. All screening evaluations must be 
completed and reviewed to confirm that potential suitable patients meet all eligibility criteria. 
Upon completion of the screening evaluation, patients meeting all the eligibility criteria will 
be enrolled and, for Phase I patients, dose level assigned; the enrollment number will be 
centrally assigned and maintained throughout all the study duration. Patients who do not meet 
all the eligibility criteria will be declared screening failure. 
Screening and enrollment numbers assignment and, for Phase I patients only, also dose level, 
will be centrally managed by the Sponsor within one working day. The investigator will 
maintain a screening and enrollment log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
No study drug will be dispensed to a patient until the entire registration/enrollment process is 
completed. It is recommended to start the treatment within 1-4 days from patient enrollment. 
For the phase I portion of the study, the Sponsor will notify all the participant sites of the 
inclusion of a new patient and will inform them of the next possible enrollment date. The 
enrollment will be competitive among the participating sites. 
8.1. Screening Procedures 
Following the obtaining of the ICF, in order to get the patient’s screening number, the 
Investigator will enter the information required in a web application made available to centers 
by the Sponsor (details are reported in the Study Manual). 
The screening number will be sequential for the center where the patient has been recruited. 
The screening number assignment is automatically notified by e-mail. 
In case the web application is not available because of any reason, the Investigator will enter 
the information required in a paper registration/enrollment form and fax/email it to the 
Sponsor (details are reported in the Study Manual). 
 
 
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8.2. Enrollment procedures 
Upon completion of the screening evaluation, the Investigator will enter the information in 
the web application, confirming patient’s eligibility or declaring the patient as screening 
failure; patients meeting all the eligibility criteria will be enrolled. The enrollment number 
will be assigned centrally and automatically notified by e-mail (details are reported in the 
Study Manual). 
The enrollment number will be sequential regardless of the center where the patient has been 
recruited. 
In case the web application is not available because of any reason, the Investigator will enter 
the information required in a paper registration/enrollment form and fax/email it to the 
Sponsor (details are reported in the Study Manual). 
The eligibility of a patient is an Investigator’s responsibility. Verification of the confirmed 
eligibility will be performed by the Sponsor or authorized personnel delegated by the Sponsor 
during the study. 
9. TREATMENT  
9.1. Product 
9.1.1. Description 
NMS-01940153E is a 
 
 
, potent small 
molecule inhibitor of MPS1 kinase, critical player in the control of mitosis. 
NMS-01940153E is provided as 30 mg salt, 
 
 
 Each vial (primary packaging) is packaged in a 
labeled single small carton (secondary packaging). The labeling of packages complies with 
regulatory requirements of countries involved in the study as well as recommendations 
provided in Annex 13 of the European Guide to Good Manufacturing Practice. 
9.1.2. Drug Preparation/Administration/Dispensing 
NMS-01940153E will be administered only at the investigational site and for no reason will 
be delivered to the patient for administration outside the reference investigational site. The 
appropriate amount of NMS-01940153E to be administered will be calculated based on the 
body surface area (BSA) of each individual patient, calculated based on Mosteller formula: 
BSA (m2) = [height (cm) x weight (kg)/3600]1/2 
The 30 mg/vial powder for solution for infusion will be reconstituted with 10 mL of sterile 
water for injection; the freeze-dried cake will easily dissolve by manual shaking in not more 
than one minute. The obtained solution will be further diluted with 0.9% Sodium Chloride for 
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injection, according to the dose of NMS-01940153E to be administered. Details are reported 
in the Investigational Medicinal Product (IMP) module of the study manual. 
Only qualified personnel familiar with procedures that minimize undue exposure to them and 
to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents. 
9.1.3. Procedure for Handling Drug Spills 
As NMS-01940153E is a cytotoxic agent, drug handling precautions as for cytotoxic agents 
should be followed. Avoid contact or inhalation. In case of skin contact, the affected area 
should be washed with soap and plenty of water. Any contaminated clothing should be 
removed. In case of eye-contact, rinse thoroughly with plenty of water. Seek medical advice 
as soon as possible. In case of accidental spill, caregivers should be instructed to wear 
protective (waterproof) gloves. Collect the spilled substance in a suitable container for 
disposal in accordance with the local regulations concerning handling and disposal of 
cytotoxic materials. Once the spilled drug has been collected, use a detergent and then wash 
thoroughly with plenty of water for removal. 
9.1.4. Storage and Stability 
The IMP must be stored in a locked room that can be accessed only by the Pharmacist, the 
Investigator, or another duly designated person, in the original packaging, at controlled room 
temperature (not above +25°C and 77°F) conditions. 
On the basis of the available stability results, a shelf-life of 60 months at controlled room 
temperature not above +25°C and 77°F is assigned to the IMP. 
The NMS-01940153E reconstituted/diluted solutions can be stored for not more than 4 hours 
at room temperature and ambient light conditions prior to patient administration. However, it 
is recommended to prepare the reconstituted/diluted solutions just before or close to the 
infusion time (further details are reported in the IMP module of the study manual). 
9.1.5. Source of drug 
NMS-01940153E will be manufactured, packaged and distributed by NerPharMa S.r.l., 
(Nerviano, Italy) in compliance with good manufacturing practice (GMP) guidelines and 
under Sponsor’s direction. NMS-01940153E re-supplies may be obtained by contacting the 
Sponsor, according to instructions detailed in the IMP module of the study manual. 
9.1.6. The study product 
The study product must not be used outside the context of this protocol. Under no 
circumstances should the Investigator or site personnel supply study product to other 
Investigators or clinics, or allowed the supplies to be used other than as directed by this 
protocol without authorization from the Sponsor. 
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The study drug must be administered to patients, according to study schedule, until the criteria 
for withdrawal are met, as detailed in Section 10. Drug accountability should continue to be 
performed and documented until the patient’s last dose of NMS-01940153E. 
Adequate records on receipt, use, return, destruction or loss, or other disposition of medication 
must be maintained. Drug accountability will be provided by the investigational site by using 
either specific drug accountability forms provided by the Sponsor or records used by the 
pharmacy at the investigational site and agreed upfront with the Sponsor. In either case, 
information describing study drug supplies and their disposition, patient by patient, must be 
provided, signed by the Investigator (or the pharmacist or other person who dispensed the 
drug). Details are provided in the IMP module of the study manual. 
After verification by the study monitor and upon authorization of the Sponsor, the unused 
drug vials may be destroyed at the site as dictated by the appropriate standard procedures of 
the participating institution and destruction must be documented; alternatively, all unused 
drug vials will be returned to the Manufacturer who will provide, on behalf of the Sponsor, to 
send them to destruction. All used drug vials should be discarded according to the standard 
institutional policy. 
9.2. Treatment Administration 
9.2.1. Treatment Dose and Schedule  
NMS-01940153E will be administered IV for 3 consecutive weeks on days 1, 8, 15 followed 
by 1 week of rest, in a 28-day cycle. The total dose to be administered will be calculated based 
on patient’s BSA (see Section 9.1.2). The duration of infusion will be dependent on the total 
dose to be administered: 
• 1 hour infusion if ≤255 mg are administered 
• 1 hour 30 minutes infusion if >255 mg but <375 mg are administered 
The starting dose for the Phase I portion of the study is 100 mg/m2/week, then according to 
the observed safety profile, dose increments of 25-35% will be applied until the MTD is 
reached. In presence of unacceptable toxicity observed at 100 mg/m2/week, a lower dose level 
by 25-35% may be tested. 
In the Phase II portion of the study, NMS-01940153E will be administered at the RP2D 
defined in the Phase I, as starting dose (see Section 5.2 for definitions). 
9.2.2. Duration of Treatment  
Patients may continue on study treatment until disease progression, unacceptable toxicity, 
withdrawal of consent by the patient or other discontinuation criteria are met (see Section 10). 
The study will be closed once that the last patient has left the study. 
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9.2.3. Dose Modifications 
9.2.3.1. Dose Reductions/Treatment discontinuations 
Dose reductions/treatment discontinuations may occur as a consequence of drug-related 
toxicities, during a cycle or at the start of a new cycle. All dose reductions/treatment 
discontinuations should be based on the most severe toxicity observed in the previous cycle 
and attributable to the study drug (according to the NCI CTCAE v 5.0). In the event of 
multiple toxicities, the dose reduction/treatment discontinuation should be based on the worst 
toxicity observed. 
Any modification to the NMS-01940153E dose should be documented in the eCRF. 
During treatment, doses can be de-escalated only twice, otherwise patients would have to be 
withdrawn. 
Doses reduced for drug-related toxicity should generally not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose according to Table 6. However, intra-patient re-
escalation back to the previous dose level may be permitted at the discretion of the Investigator 
after discussion with the Sponsor.  
Recommended dose reductions or discontinuation criteria during the treatment cycle and at 
the start of the subsequent cycle are shown in Table 6. 
9.2.3.2. Re-treatment Criteria and Cycle Delay 
A new cycle of treatment may begin when hematological and non-hematological toxicities 
are Grade ≤1 or have recovered to baseline values. 
If these conditions are not met, treatment should be delayed for 1 week to allow for recovery. 
If, after 1-week delay, re-treatment criteria are met, then the new cycle can be initiated with a 
starting dose defined based on the toxicities observed in the previous cycle as outlined in the 
Table 6.  
If, after this period, toxicities do not recover to the pre-defined level, the patient will be 
withdrawn from the treatment, unless the Investigator believes treatment continuation is in 
the patient best interest. In this case, a maximum delay of 2 weeks (up to day 42 from cycle 
start) will be allowed. 
 
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Table 6. Dose Reductions/Treatment Discontinuations for NMS-01940153E Based on 
the Worst Grade (as per NCI CTCAE Criteria, Version 5.0) Observed During a 
Treatment Cycle and in the Prior Treatment Cycle 
Toxicity 
Dose Adjustment during treatment 
cycle 
Next cycle Starting Dose 
Hematological Toxicities 
Neutropenia Grade 3 
 
Omit dose; when resolved to ≤ Grade 
1 within the same cycle, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
 
Neutropenia Grade 4 
Omit dose; when resolved to ≤ Grade 
1 within the same cycle, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
Febrile Neutropenia 
Omit dose; when resolved, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
Thrombocytopenia Grade 3 
associated with bleeding or 
thrombocytopenia Grade 4 
Omit dose; when resolved to ≤ Grade 
2 within the same cycle, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
Anemia Grade 3 
Omit dose; when resolved to ≤ Grade 
2 within the same cycle, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
Anemia Grade 4 
Study treatment discontinuation. 
Study treatment discontinuation. 
Other Grade 3 Hematologic 
Toxicities 
Omit dose; when resolved to ≤ Grade 
2 within the same cycle, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
Other Grade 4 Hematologic 
Toxicities 
Study treatment discontinuation. 
Study treatment discontinuation. 
Nausea and/or Vomiting 
Grade  3 despite optimal 
management of the event §‡ 
Omit dose; when resolved to ≤ Grade 
2 within the same cycle, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
Diarrhea 
Grade 2 despite optimal 
management of the event § 
Omit dose; within the same cycle 
decrease one dose level. 
Start at or maintain the decreased 
dose level. 
Grade  3 despite optimal 
management of the event § 
Omit dose; when resolved to ≤ Grade 
2 within the same cycle, decrease 
one dose level. 
Start at or maintain the decreased 
dose level. 
Neurologic Toxicities (except insomnia/paraesthesia) 
Grade 2 
Omit dose; when resolved to ≤ Grade 
1, decrease one dose level. 
Start at or maintain the decreased 
dose level. 
Grade > 2 
Consider discontinuation of study 
treatment based on risk/benefit 
assessment #. 
Consider discontinuation of study 
treatment based on risk/benefit 
assessment #. 
Other Non-Hematological Toxicities (except alopecia) 
Intolerable or persistent Grade 2 
adverse events 
Omit dose; when resolved to ≤ Grade 
2, maintain the dose level at first 
occurrence; at second occurrence, 
omit dose; when resolved to ≤ Grade 
2, decrease one dose level. . 
At second occurrence, start at or 
maintain the decreased dose level. 
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Table 6. Dose Reductions/Treatment Discontinuations for NMS-01940153E Based on 
the Worst Grade (as per NCI CTCAE Criteria, Version 5.0) Observed During a 
Treatment Cycle and in the Prior Treatment Cycle 
Toxicity 
Dose Adjustment during treatment 
cycle 
Next cycle Starting Dose 
Grade 3 
Omit dose; when resolved to ≤ Grade 
2, decrease one dose level. 
Start at or maintain the decreased 
dose level. 
Grade 4 
Omit dose; when resolved to ≤ Grade 
2, decrease one dose level or 
consider study treatment 
discontinuation # 
Start at or maintain the decreased 
dose level or consider study 
treatment discontinuation # 
Grade  3 hypersensitivity 
reaction suggestive of 
anaphylactic reaction # 
Study treatment discontinuation 
Study treatment discontinuation. 
§ For prophylaxis and management of the events, see details in Supportive Care Sections 9.2.7. 
‡ lasting longer than 48h without resolution to grade 2 or better and judged at least possibly related to NMS-01940153E. 
 # Investigator to discuss risk/benefit with Sponsor, if positive, decrease one dose level. 
9.2.4. Extension Treatment 
Not applicable. 
9.2.5. Overdose Instructions 
There are no known antidotes for NMS-01940153E overdose. All cases of overdose 
[associated or not to an adverse event/serious adverse event (AE/SAE)] and medication errors 
accompanied by an AE/SAE, should be notified, using the SAE form, to the Sponsor 
Pharmacovigilance immediately (i.e. within 24 hours) according to procedures described in 
part 11.5.1.7. Study monitor should be also contacted to discuss the details of any overdose. 
Whether or not the overdose/medication error is accompanied by an AE, as determined by the 
Investigator, the overdose/medication error and, if applicable, any associated AE must be 
captured on the AE eCRF page (refer to Safety Assessments, Section 11.5, for further details). 
9.2.6. Unblinding 
Not applicable. 
9.2.7. Concomitant Medications and Other Therapy 
Any medication the patient takes other than the study treatment, including herbal and other 
non-traditional remedies, is considered a concomitant medication. All information concerning 
concomitant medication taken (started or completed) up to 28 days before the start of 
treatment with NMS-01940153E and within 28 days (and, if applicable, no more than 35 days) 
from last study drug administration, should be collected on the electronic case report form 
(eCRF): name, active ingredient, reason for use, route of administration, strength and unit, 
frequency or total daily dose, start and stop dates. Any change in the dosage or regimen of a 
concomitant medication must be recorded in the eCRF. 
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Prior treatments for the disease under study are to be collected on separate and appropriate 
forms of the eCRF and should cover the entire tumour history. 
Directives for supportive care of the patients are outlined below and could be adapted 
according to institutional practices; however they cannot ever include strong inducers of 
flavin-containing monooxygenase 1 (FMO1), FMO3 as well as sensitive cytochrome 3A4 
(CYP3A4) substrates, CYP3A4 and BCRP (breast cancer resistance protein) substrates with 
narrow therapeutic index (NTI). See Appendix 3 and Appendix 4 for details. 
9.2.7.1. Antiemetics Support 
Mild nausea and vomiting have been reported in the FIH study (EudraCT 2014-002023-10). 
Among 38 patients who received NMS-01940153E, nausea was reported in 12 patients 
(31.6%), with only one patient experiencing grade 3. Grade 1-2 vomiting was reported in 9 
patients (23.7%). 
Prophylactic therapy with antiemetics, administered according to hospital guidelines, is 
allowed including during cycle 1, if deemed appropriate. 
Antiemetic therapy can be administered at Investigator’s discretion whenever needed, 
including during cycle 1. 
9.2.7.2. Antidiarrheal Support 
The use of antidiarrheal agents is allowed according to hospital guidelines along with 
antibiotic treatment and IV hydration, if indicated. Patients should be instructed to refer to the 
centre in case of: diarrhoea lasting > 24 hours despite optimal supportive care or diarrhea with 
fever; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or 
faintness and inability to take liquids by mouth due to nausea and vomiting. 
9.2.7.3. Hematopoietic Support 
Red blood cell and/or platelets transfusion: during treatment should be considered at the 
Investigator’s discretion in patients with significant anaemia and/or thrombocytopenia; 
transfusions are however not allowed within 72h before treatment start. Folates may be 
indicated also for anaemia treatment. 
Hematopoietic growth factors 
In the dose escalation part, prophylactic use of G-CSF or initiation of erythropoietin in Cycle 1 
is not permitted but may be instituted in Cycle ≥ 2 in patients who are having difficulty with 
severe neutropenia or anemia. Patients who have been treated for  4 weeks with 
erythropoietin prior to the first cycle may continue the existing treatment.  
Growth factors may be used as medically indicated in patients with relevant neutropenic 
complications, such as tissue infection, sepsis, etc., or anemia, at the Investigator’s discretion. 
Patients with neutropenic fever or infection should be hospitalized promptly for IV antibiotic 
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therapy and may receive therapeutic CSFs as appropriate. Treatment of relevant neutropenic 
complications (e.g. tissue infection, sepsis, etc.) is left at the Investigator’s discretion and 
should be done according to the hospital guidelines for treating these types of events. 
9.2.7.4. Prophylaxis for Polysorbate 80 intolerance 
Intolerance: prophylactic treatment is not allowed before Cycle 1. In case the toxicity profile 
emerging during the study suggests that there might be signs of intolerance to polysorbate 80, 
prophylaxis with antihistaminic or corticosteroids according to centre practices could be 
implemented. 
9.2.7.5. Other Permitted Concomitant Medications 
Therapies considered necessary for the patient’s wellbeing may be given at the discretion of 
the Investigator, i.e. chronic treatments for concomitant medical conditions, as well as agents 
required for life-threatening medical problems, analgesics etc. according to the drug-drug 
interaction information. In particular, strong inhibitors of FMO1 and FMO3, moderate 
substrates of CYP3A4 and CYP3A4/BCRP substrates with no NTI should be used with 
caution (see Appendix 4). 
Precaution should be used in treatment of NMS-01940153E with concomitant drugs that are 
known to prolong QT or QTc intervals, since the potential effect of study drug on QT 
prolongation has not been fully evaluated in humans. The Investigator should consult 
individual labels for concomitant medication. If medically indicated, a cardiology consult 
should be obtained. 
Whenever possible the administration of drugs that may cause drug-drug interaction should 
not be done concomitantly with NMS-01940153E. 
Patients should be advised to contact the treating physician before starting any new drug. 
9.2.7.6. Other Anticancer or Experimental Therapy 
No other approved or investigational anticancer treatment will be permitted during the study 
treatment period, including chemotherapy, immunotherapy, biological response modifiers, 
and hormones. 
9.2.7.7. Concomitant Radiotherapy  
Palliative radiotherapy to specific sites is permitted if considered medically necessary by the 
treating physician. It is recommended to avoid radiotherapy for at least 5 days after the last 
dose of NMS-01940153E and to contact the Sponsor. Also, the irradiated area should be as 
small as possible, and ≤25% of the bone marrow reserve (see Appendix 5). During the period 
of irradiation and for 2 weeks after, therapy with NMS-01940153E should be withheld. If 
irradiation-related toxicities (other than xerostomia) have not normalized to pre-irradiation 
levels after these 2 weeks of rest, the patient should be removed from the study. Irradiated 
lesions will be followed for disease progression. In case radiotherapy involving >25% bone 
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marrow reserve is needed, the patient will be considered as having progressed and should be 
removed from treatment. During the study, radiotherapy for active brain metastases will 
represent a progression. 
10. SUBJECT WITHDRAWAL FROM STUDY PARTICIPATION 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, 
or administrative reasons. 
If the patient does not return for a scheduled visit, every effort should be made to contact 
him/her. In any circumstance, every effort should be made to document patient outcome, if 
possible. The Investigator should inquire about the reason for withdrawal, request the patient 
to return for a final visit, if applicable, and follow-up with the patient regarding any 
unresolved adverse events. 
If the patient withdraws consent for disclosure of future information, no further evaluations 
should be performed and no additional data should be collected. The Sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 
Patients may continue with therapy unless any of the following occurs: 
• 
Disease progression by RECIST 1.1 at any time, unless there is reasonable evidence of 
clinical benefit to justify continuation on treatment, to be discussed with the Sponsor; 
• 
Unacceptable drug-related toxicities incompatible with continuation of treatment with 
NMS-01940153E according to the judgment of the Investigator, even at a reduced dose; 
• 
Any medical event requiring administration of an unauthorised concomitant treatment if 
it interferes with the study evaluations and/or if it jeopardises patient’s safety (see Section 
9.2.7); 
• 
Change in the patient’s medical status (including pregnancy) such that the Investigator 
believes that patient safety may be compromised or that it would be in the best patient’s 
interest to stop treatment; 
• 
Occurrence of permanent or significant incapacity or disability; 
• 
Treatment delay for >1 week from day 28 of any cycle due to treatment related toxicity, 
unless the investigator believes treatment continuation is in the best patient’s interest. In 
this case a maximum delay of 2 weeks is allowed; 
• 
More than two dose de-escalations required; 
• 
Substantial deviation from specified inclusion or exclusion criteria or non-compliance by 
the patient with protocol requirements; 
• 
Patient’s refusal to continue study treatment; 
• 
Withdrawal of consent; 
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• 
Patient lost to follow up; 
• 
Death; 
• 
Study terminated by the Sponsor. 
 
Patients will be withdrawn from the study in case of: 
• 
Withdrawal of consent; 
• 
Patient lost to follow up; 
• 
Death; 
• 
Study terminated by the Sponsor. 
Data to be collected for the end of study treatment/withdrawal are described in the Schedule 
of Events, reported in Section 7. 
After treatment discontinuation patients will be followed for progression, if not progressed 
earlier, until the start of a new anticancer therapy, and for survival. Patients will be followed 
for at least 28 days after the last dose of study drug for adverse events and every 2 months up 
to death, for secondary efficacy endpoint purpose. 
 
 
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11. ASSESSMENTS  
11.1. Timing of Assessments 
Section 7 (SCHEDULE OF EVENTS) summarizes information on the timing of study 
assessments to be performed during Phase I and Phase II. Protocol waivers or exemptions are 
not allowed. 
11.2. Disease Assessments 
11.2.1. TNM Staging 
TNM Staging will be performed at enrollment according to “American Joint Committee on 
Cancer (AJCC) TNM Staging for Hepatocellular Cancer (8th ed., 2017)” [18];  
Histological grading and fibrosis score, as defined by Ishak, will be requested, if available. 
Table 7. Definitions for T, N, M 
T 
Primary Tumor 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
T1 
Solitary tumor ≤2 cm, or >2 cm without vascular invasion 
T1a 
Solitary tumor ≤2 cm 
T1b 
Solitary tumor >2 cm without vascular invasion 
T2 
Solitary tumor >2 cm with vascular invasion, or multiple 
tumors, none >5 cm 
T3 
Multiple tumors, at least one of which is >5 cm 
T4 
Single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic 
vein, or tumor(s) with direct invasion of adjacent organs other than the gallbladder or with 
perforation of visceral peritoneum 
N 
Regional Lymph Nodes 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Regional lymph node metastasis 
M 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
11.2.2. Barcelona Clinic Liver Cancer (BCLC) Staging System 
BCLC [19] (Table 8) will be collected at enrollment: 
 
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Table 8. Definitions for prognostic groups 
Very early stage (0) 
• Single ≤2 cm 
• Preserved liver function, PS 0 
Early stage (A) 
• Single, or ≤3 nodules each ≤3 cm 
• Preserved liver function, PS 0 
Intermediate stage (B) 
• Multinodular 
• Preserved liver function, PS 0 
Advanced stage (C) 
• Portal invasion and/or extrahepatic spread 
• Preserved liver function, PS 1-2 
Terminal stage (D) 
• Any tumor burden 
• End stage liver function, PS 3-4 
 
Additional info on tumoral characteristic will be requested when available. 
11.3. Efficacy Assessments 
The determination of antitumor efficacy will be based on objective tumor assessments made 
according to RECIST guideline (version 1.1) [17] and to the modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) guideline [20]. 
A summary of RECIST 1.1 and mRECIST is reported in the following sections. 
11.3.1. Tumor Imaging 
Baseline tumor imaging (by CT scan, PET or MRI) has to be performed at screening within 
28 days prior to the treatment start. On treatment, tumor assessments will be performed every 
even month (i.e., end of Cycle 2, 4, 6 etc) or whenever a clinical deterioration is observed and 
at the end of last cycle, unless a tumor assessment was performed within the previous 4 weeks. 
In patients withdrawn for causes other than disease progression, during follow up, regular 
tumor imaging assessments will be performed every 2 months, until PD or until a new 
antitumor therapy starts. On treatment, a time window of -2/+5 days is allowed. 
Patients with responding tumors (complete or partial response) must have response confirmed 
at least 4 weeks after the first documentation of response. 
CT scan is the desirable method for lesion measurement. MRI is acceptable provided that the 
size of the measurable lesion is twice the slice thickness of the MRI. MRI should be performed 
at pre-treatment in case of known or suspected CNS involvement.  
According to RECIST, the same method and technique (CT scan or MRI) should be used to 
characterize each identified and reported lesion at baseline and during the following 
assessments. 
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Imaging-based evaluation should be preferred to clinical examination when both could be 
used to assess the antitumor effect of the treatment.  
According to mRECIST, tumor assessment should be performed with the administration of 
intravenous contrast to obtain a dual-phase imaging of the liver. To prevent possibly allergic 
reactions to intravenous Contrast Medium (CM), patients with previous reaction(s) to CM, 
asthma even drug controlled and/or food or drug allergies will be treated with a premedication 
(corticosteroid).  
Patients can be followed with either contrast-enhanced spiral CT (preferably with use of 
multi-slice scanners) or contrast-enhanced dynamic MRI. Each modality has advantages and 
disadvantages, and mRECIST does not recommend one modality over another.  
However, it is recommended that the same imaging modality be used throughout the study. 
Ultrasound – including contrast-enhanced ultrasound – is not recommended for the general 
use of mRECIST. 
PET/CT is not accepted for treatment assessment in guidelines.  
Obtaining a pre-contrast scan is useful but not mandatory for CT. Conversely, establishing 
the intrinsic T1 intensity of tumour lesions at baseline is recommended in MRI, in order to 
infer subsequent contrast enhancement or perform subtraction imaging. 
The administration of intravenous contrast is required for all CT or MRI studies if not 
medically contraindicated. In contrast-enhanced studies, it is crucial to time the contrast 
administration so that high-quality arterial-phase imaging is obtained on the first run, and 
high-quality portal venous-phase imaging is obtained on the second run. An arterial phase that 
is acquired too early (i.e., when the hepatic arterial branches are fully enhanced but the portal 
vein is not yet enhanced) may be inadequate since the degree of enhancement of HCC is 
usually higher in the late arterial phase (i.e., when the hepatic arterial branches are fully 
enhanced, the portal vein is also enhanced, but the hepatic veins are not yet enhanced). 
Delayed imaging acquired two to five minutes after injection may be useful, but it is not 
mandatory and should be done only if it is part of clinical practice. In MRI studies, when using 
a hepatobiliary contrast agent instead of an extracellular contrast agent, the hepatobiliary 
phase acquired about 20 min after injection of gadoxetate disodium may be used to aid lesion 
detection and diagnostic confidence [20]. 
All patients’ files and scans must be available for source verification. 
11.3.1.1. Central Imaging Facility 
A central imaging facility may evaluate imaging studies and supportive clinical data in a 
central and independent fashion as central review of tumor response assessments. The facility 
will not perform clinical evaluations. The central imaging facility may be chartered to 
establish radiographic progression and may consider selected clinical data solely to aid in the 
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interpretation of radiographic images. All radiological scans, acquired at all scheduled time 
points and any additional (unscheduled) radiological images acquired to evaluate for potential 
progressive disease, must be maintained as a copy of digital data for the retention period 
applicable to the protocol duration, GCPs, and federal, international and/or state legal as well 
as medical requirements. The Sponsor and/or designee may retain the media until or beyond 
study completion. 
11.3.1.2. Measurability of Tumor Lesions 
At baseline tumor lesions will be categorized by the Investigator as measurable or non-
measurable by the RECIST guideline (version 1.1) criteria as described below: 
Measurable: 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). In case of MRI, the 
size of the measurable lesion must be twice the slice thickness of the MRI and a minimum 
of 10 mm. 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).  
• 20 mm by chest X-ray. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Non-Measurable: 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with 10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions:  
• Bone scan, Positron Emission Tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
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• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable.  
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• “Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
According to mRECIST, the measurement of the longest viable tumor diameter for the 
assessment of response can be only applied in case of typical lesions. Every effort should be 
made to time the contrast administration so that high-quality arterial-phase imaging is 
obtained throughout the liver on the ﬁrst run, and high-quality portal venous-phase imaging 
is obtained throughout the liver on the second run. Delayed imaging obtained in the 
equilibrium phase may be useful, but it is not mandatory and should be done only if it is part 
of clinical practice. 
Conversely, for non-enhancing atypical lesions, as well as for any extra-hepatic neoplastic 
niches, the measurements of the longest overall tumor diameter as per conventional RECIST 
should prevail. 
11.3.1.3. Recording Tumor Measurements 
Target lesions. When more than one measurable lesion is present at baseline, all lesions up 
to a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and measured 
at baseline (this means in instances where patients have only one or two organ sites involved 
a maximum of two and four lesions respectively will be recorded). Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself to 
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reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 
Pathological nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of 15 mm by CT scan. Only the short axis of these 
nodes will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or 
coronal). The smaller of these measures is the short axis. For example, an abdominal node 
which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
According to mRECIST a target lesion should meet all the following criteria: 
• The lesion can be classiﬁed as a RECIST measurable lesion (i.e., the lesion can be 
accurately measured in at least one dimension as 1 cm or more). 
• The lesion is suitable for repeat measurement. 
• The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or MRI. 
The relevant number of target lesions for the investigator-assessed mRECIST assessment is 
recommended [20] as a maximum of 2 target lesions per organ and 5 target lesions in total. 
Other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. 
It is important to point out that only well-delineated, arterially enhancing lesions can be 
selected as target lesions for mRECIST.  
Conversely, for non-enhancing atypical lesions, as well as for any extrahepatic neoplastic 
niches, the measurements of the longest overall tumor diameter for the assessment of response 
as per conventional RECIST should prevail. 
Non-target lesions. All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline, including pathological lymph nodes with short 
axis 10 mm but <15 mm (nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed). 
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Measurements are not required, and these lesions should be followed as “present”, “absent”, 
or in rare cases “unequivocal progression”. In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on the case record form (e.g. “multiple 
enlarged pelvic lymph nodes” or “multiple liver metastases”). 
According to mRECIST, inﬁltrative-type HCC should be considered as a non target lesion 
when the mass shows ill-deﬁned borders and therefore does not appear to be suitable for 
accurate and repeat measurements.   
11.3.1.4. Target Lesions Tumor Response 
Complete response (CR) is defined as disappearance of all target lesions and reduction in 
short axis to <10 mm of any pathological lymph nodes (whether target or non-target). 
Partial response (PR) is defined as at least 30% decrease in the sum of the diameters of the 
target lesions, taking as a reference the baseline sum diameters. 
Progressive disease (PD) is defined as at least 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
According to mRECIST treatment response for target lesions will be defined as follows:  
CR:  the disappearance of any intratumoral arterial enhancement in all target lesions. 
PR: at least a 30% decrease in the sum of diameters of viable (contrast enhancement in the 
arterial phase) target lesions, taking as reference the baseline sum of the diameters of target 
lesions. 
PD: an increase of at least 20% in the sum of the diameters of viable (enhancing) target 
lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target 
lesions recorded since the treatment started. To note that, consistent with RECIST and 
mRECIST criteria, only radiographic progression, not clinical progression, determines the 
calculation of RECIST PD or mRECIST PD.SD: any cases that do not qualify for either partial 
response or progressive disease. 
Since for HCC the measurement of the longest diameter of the viable tumor may be 
challenging in lesions showing partial internal necrosis, according to mRECIST, the following 
points should be taken into account in such cases: 
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• The measurement of the viable tumor should be performed on CT or MRI obtained in the 
arterial phase, when the contrast between viable vascularized tumor tissue and non 
enhancing necrotic tissue is the highest. 
• The longest diameter of the viable tumor is not necessarily located in the same scan plane 
in which the baseline diameter was measured: a thorough careful evaluation of the CT or 
MRI scans is required. 
• The measurement of the viable tumor diameter should not include any major intervening 
areas of necrosis. 
11.3.1.4.1. Special notes on the assessment of target lesions 
Lymph nodes: lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of <10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become “too small to measure”: while on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being ‘too small to measure’. When this occurs, it is important that a value is recorded on the 
case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned. (Note: It is 
less likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retro-peritoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived 
from the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). 
The measurement of these lesions is potentially non-reproducible, therefore providing this 
default value will prevent false responses or progressions based upon measurement error. To 
reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment: when non-nodal lesions “fragment”, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
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truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the “coalesced lesion”. 
11.3.1.5. Non Target Lesions Tumor Response 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete response (CR) is defined as the disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 
mm short axis). 
Non-CR/Non-PD is defined as a persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive disease (PD) is defined as unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
When effusions are known to be a potential adverse effect of treatment, the 
cytological/histological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or SD is 
mandatory to differentiate between response or SD and PD. 
Tumor necrosis should be taken into account when assessing the response of non-target 
lesions. According to mRECIST the disappearance of intratumoral arterial enhancement in 
non-target lesions should be considered equivalent to the disappearance of non-target lesions, 
and therefore, should declare complete response of non-target lesions. The persistence of 
intratumoral arterial enhancement in one or more non-target lesions should be considered 
equivalent to persistence of one or more non-target lesions, and therefore, should declare 
incomplete response/stable disease. The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions should declare progressive disease. 
For patients with HCC and cirrhosis the mRECIST provides the following special 
recommendations for the assessment of tumor response in non-target lesions:  
1. Portal vein thrombosis. Malignant portal vein thrombosis should be considered a non 
measurable lesion due to the difﬁculty in performing consistent measurements of the 
malignant thrombus during the course of the treatment. Measurements of the extent of the 
malignant thrombus may be impaired by the possible presence of a bland component of 
the thrombosis. 
2. Portal hepatic lymph node. Lymph nodes detected at the portal hepatic can be considered 
as malignant if the lymph nodes short axis is at least 20 mm. Evidence of reactive lymph 
nodes at the porta hepatis, in fact, is a common ﬁnding in patients with cirrhosis regardless 
of the presence of an HCC. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. 
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3. Pleural effusion and ascites. As per original RECIST, cytologic conﬁrmation of the 
neoplastic nature of any effusion that appears or worsens during treatment is required 
when the measurable tumor has met criteria for response or stable disease. Under such 
circumstances, the cytologic examination of the ﬂuid collected will permit differentiation 
between response or stable disease (an effusion may be aside effect of the treatment) and 
progressive disease (if the neoplastic origin of the ﬂuid is conﬁrmed). The mRECIST for 
HCC panel of experts considered this issue to be of high importance in the setting of HCC 
in cirrhosis. The emergence or the increase in ascites is a common event during the course 
of treatment in a cirrhotic patient, which may be due to worsening of the underlying 
chronic liver disease and be unrelated to cancer progression. Other effusions, such as 
pleural effusion, may also be unrelated to cancer progression and be caused by the liver 
insufﬁciency. Thus, the mRECIST for HCC emphasizes that cytopathologic conﬁrmation 
of the neoplastic nature of any effusion (particularly ascites) that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or 
stable disease. It has to be underlined that peritoneal carcinomatosis is a very rare event 
in HCC. 
11.3.1.5.1. Special notes on assessment of progression of non-target disease 
To achieve “unequivocal progression” on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
11.3.1.6. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no speciﬁc criteria for the 
identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or ﬁndings thought to represent something other than tumour (for example, some 
‘new’ bone lesions may be simply healing or ﬂare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. A lesion 
identiﬁed on a follow-up study in anatomic allocation that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. If a new lesion is equivocal, 
for example because of its small size, continued therapy and follow-up evaluation will clarify 
if it represents truly new disease. If repeat scans conﬁrm there is deﬁnitely a new lesion, then 
progression should be declared using the date of the initial scan.  
Characterization of a newly detected focal liver lesion as true HCC is a challenging issue in 
the setting of cirrhosis because pathologic abnormalities related to cirrhosis changes, such as 
large regenerative nodules and dysplastic nodules, may be indistinguishable from a small 
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tumor. Moreover, the presence of perfusion abnormalities resulting in areas of abnormal liver 
enhancement in a cirrhotic liver may ultimately mimic or conceal focal liver lesions; hence, 
perfusion abnormalities represent an additional major source for interpretation errors. 
According to mRECIST the assessment of tumor progression was observed when: 
a) A newly detected hepatic nodule will be classiﬁed as HCC, and therefore will be declared 
as evidence of progression, when its longest diameter is at least 1 cm and the nodule shows 
the typical vascular pattern of HCC on dynamic imaging, that is, hypervascularization in 
the arterial phase with washout in the portal venous or late venous phase.  
b) Liver lesions larger than 1 cm that do not show a typical vascular pattern can be diagnosed 
as HCC by evidence of at least 1-cm-interval growth in subsequent scans. 
c) An individual radiologic event will be adjudicated in retrospect as progression at the time 
it was first detected by imaging techniques, even if strict criteria were fulfilled only on 
subsequent radiologic testing. 
11.3.1.7. Confirmation of Tumor Response 
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed ≥4 weeks after the criteria for response are first met by 
the same tumor imaging technique used at baseline and on treatment (e.g., CT scan or MRI). 
In case of SD, measurements must have met the SD criteria at least once after study entry at 
the minimum interval of 8 weeks. 
11.3.1.8. Determination of Overall Response by RECIST (version 1.1) 
When both target and non-target lesions are present, individual assessments will be recorded 
separately. The overall assessment of response will involve all parameters as depicted in 
Table 9. 
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Table 9. Response Criteria by RECIST 1.1* 
Target Lesion1 
Non-Target Lesion2 
New Lesion3 
Overall Response4 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any response 
Yes or No 
PD 
Any response 
PD 
Yes or No 
PD 
Any response 
Any response 
Yes 
PD 
1 Measurable lesions only.  
2 May include measurable lesions not followed as target lesions or non-measurable lesions. 
3 Measurable or non-measurable lesions. 
Abbreviations: CR = complete response, PD = progressive disease, PR = partial response, SD = 
stable disease, NE = not evaluable. 
 
* According to RECIST 1.1, patients with non-target disease only will be classified as CR if no 
new lesions appear and baseline lesions completely disappear;  
non-CR/non-PD, in case of no new lesions and neither CR or unequivocal PD in baseline 
lesions; 
PD if new lesions appear or baseline lesions show unequivocal progression 
 
11.3.1.9. Determination of Overall Response by mRECIST  
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in the 
table here below.   
In mRECIST, identical to conventional RECIST, overall patient response is a result of the 
combined assessment of target lesions, non target lesions, and new lesions.  
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Table 10. Response Criteria in mRECIST* 
Target Lesions 1 
Non-Target Lesions 2 
New Lesions 3 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any response 
Yes or No 
PD 
Any response 
PD 
Yes or No 
PD 
Any response 
Any response 
Yes 
PD 
1 Measurable lesions only  
2 May include measurable lesions not followed as target lesions or non-measurable lesions 
3 Measurable or non-measurable lesions 
Abbreviations:  mRECIST = modified Response Evaluation Criteria in Solid Tumors, CR = complete 
response, IR = incomplete response, PD = progressive disease, PR = partial response, SD = stable 
disease  
 
*According to mRECIST for HCC, in absence of target lesions, the following definitions of the criteria 
used to determine the objective tumor response for nontarget lesions apply: complete response is the 
disappearance of all nontarget lesions; incomplete response/stable disease is the persistence of one or 
more nontarget lesions; and progressive disease is the appearance of one or more new lesions and/or 
unequivocal progression of existing non target lesions.  
According to mRECIST for HCC, tumor necrosis should be taken into account when assessing the 
response of nontarget lesions. The disappearance of intratumoral arterial enhancement in nontarget 
lesions should be considered equivalent to the disappearance of 
nontarget lesions, and therefore, should declare complete response of nontarget lesions 
 
It is important to point out that appearance of one or more new lesions declares progression 
whatever the response of target and non-target lesions. 
11.3.1.10. Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation (achievement 
of both measurement and confirmation criteria, depending on the nature of the study and the 
protocol requirement). The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. 
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Table 11. Best overall response when confirmation of CR and PR required 
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
not evaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original 
CR should be changed to PR and the best response is PR. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by fine needle aspirate or biopsy before assigning a status of 
CR. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration” (see Study Manual specific data collection instructions). Of note, 
every effort should be made to document the objective progression even after discontinuation 
of treatment. Symptomatic deterioration is not a descriptor of an objective response: it is a 
reason for stopping study therapy. The objective response status of such patients is to be 
determined by evaluation of target and non-target disease. 
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11.4. Outcomes Research Assessments 
Not applicable. 
11.5. Safety Assessments 
Safety assessments include collection of AEs, SAEs, 12-lead ECGs, pregnancy tests, vital 
sign measurements, physical examinations and safety laboratory tests as outlined in the 
Schedule of events, Section 7. 
Additional safety assessments may be performed if deemed necessary by the Investigator. 
Assessment of adverse events will include type, incidence, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 
5.0) [21], timing, seriousness, and relatedness.  
11.5.1. Adverse Event Assessment 
11.5.1.1. Definition of Adverse Events 
11.5.1.1.1. Adverse Event 
According to ICH definition and EU Regulation (No. 536/2014), an AE is defined as any 
untoward medical occurrence in a subject to whom a medicinal product is administered and 
which does not necessarily have a causal relationship with this treatment. An adverse event 
can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or diagnosis temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
Any untoward medical occurrence, which occurs outside the period of patient follow-up 
defined in the protocol, is not considered an AE. Symptoms or medically significant 
laboratory or instrumental (e.g., by electrocardiography) abnormalities of a pre-existing 
condition should not be considered an AE. However, occurrence of new symptoms, laboratory 
or instrumental abnormalities, as well as worsening of pre-existing ones, is considered AEs. 
11.5.1.1.2. Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose falls into 
one or more of the following categories: 
• Results in death 
• Is life-threatening, i.e., an event which, in the view of the Investigator, placed the patient 
at risk of death at the time of event (it does not include an event which hypothetically 
might have caused death if it was more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
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• Results in persistent or significant disability/incapacity, where disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions, either reported 
or defined as per clinical judgment 
• Is a congenital anomaly/birth defect (if exposure to product just before conception or 
during pregnancy resulted in an adverse outcome in the child) 
• Is any other important medical event, i.e., may not result in death, be life-threatening, or 
require hospitalization, but based upon appropriate medical judgment, it may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the points above. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, and blood 
dyscrasias or convulsions that do not result in inpatient hospitalization. 
A non-serious adverse event is any adverse event that does not meet the criteria listed above 
or the outcome cannot be determined with the information provided. 
Each adverse event has to be classified by the Investigator as serious or non-serious.  
In this study the following do not have to be classified as SAEs: 
• Admission to hospital required by protocol. 
• Hospitalization for routine treatment or monitoring of the studied indication not associated 
with any deterioration in patient’s clinical condition. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• A procedure requiring hospitalization planned prior to starting the study treatment; must 
be documented in the Source Documents and the e-Case Report Form (e-CRF).  Prolonged 
hospitalization for a complication remains a reportable SAE. 
• Hospitalization for an elective treatment of a pre-existing condition unrelated to the 
studied indication. 
• Events definitely related to disease progression. 
However, all deaths occurring during the reporting period have to be reported as SAEs, even 
if due to disease progression. 
11.5.1.2. Unexpected Adverse Event 
An unexpected AE is one, the nature or severity of which is not consistent with the applicable 
product information that, for the present trial, is the Investigator Brochure (IB) [15]. 
11.5.1.3. Eliciting Adverse Event Information 
The Investigator has to report all directly observed AEs and all AEs spontaneously reported 
by the trial patient using concise medical terminology. In addition, each trial patient will be 
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questioned about adverse events at each clinic visit following signature of the Informed 
Consent Form. The question asked will be “Since your last clinical visit have you had any 
health problems?” 
11.5.1.4. Adverse Event Reporting Period 
The adverse event reporting period for this trial begins upon signing of informed consent and 
ends 28 days after the last study treatment administration. 
However, if a patient begins a new anticancer therapy earlier than 28 days after the last dose 
of study treatment administration, the adverse event reporting period will end at the time the 
new anticancer therapy starts. 
All the adverse events that occur in trial patients during the adverse event reporting period 
must be reported to the Sponsor, whether or not the event is considered related to the study 
treatment. 
11.5.1.5. Adverse Event Follow Up after the End of the Reporting Period 
The following events should be followed after the end of the reporting period (i.e., 28 days 
after the last study treatment administration): 
1. SAEs with outcome ‘not recovered’ or ‘unknown’ at the end of the reporting period. 
2. Non-serious events classified as related to the investigational study treatment with 
outcome ‘not recovered’ or ‘unknown’ at the end of the reporting period. 
These events should be followed until they resolve or until the Investigator determines, 
whenever possible, that they have become “chronic” or “stable”. Resolution of such events is 
to be documented on the SAE Form and/or on e-CRF. 
In addition, if after the end of the reporting period, suspected serious adverse reactions or 
deaths are reported to the Investigator and he/she believes that they are related to the IMP, it 
is the Investigator’s responsibility to report these suspected serious adverse reactions to the 
Sponsor. Such suspected serious adverse reactions will be reported using a Serious Adverse 
Event Report or by any other way chosen by the Investigator. 
11.5.1.6. Relationship to the Investigational Medicinal Product 
The relationship of the adverse event will be assessed by means of the question “Is there a 
reasonable possibility that the event may have been caused by the study drug?”  The 
Investigator should respond to this question with either ‘Yes’ or ‘No’. 
‘No’ equals to Unrelated/Unlikely, i.e. there is no reasonable possibility that the study drug 
caused the event; ‘Yes’ equals to Related, i.e. there is a reasonable possibility that the study 
drug caused the event. 
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11.5.1.7. Reporting Requirements 
Each adverse event has to be classified by the Investigator as SERIOUS or NON-SERIOUS 
(as per paragraph 11.5.1.1.2). This classification of the event determines the reporting 
procedures to be followed.  If a serious adverse event occurs, reporting will follow local and 
international regulations, as appropriate. 
If a serious adverse event occurs the Sponsor Pharmacovigilance has to be notified, using the 
designated form, within 24 hours of awareness of the event by the Investigator, by e-mail or 
by fax (here below Pharmacovigilance address/contacts). 
e-mail: Drugsafety-MPSA@nervianoms.com 
 
 
 
The initial report should be followed by submission of more detailed adverse event 
information as soon as it is available. Additional follow-up should be provided up to the 
resolution of the SAE, or the Investigator determines it has become chronic or stable (not 
recovered) or a new anticancer therapy is initiated. 
Reporting requirements for adverse events are summarized in the following table. 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
Seriousness 
Reporting Time 
Type of Report 
SERIOUS 
Within 24 hours 
Initial report on designated SAE form 
 
As soon as available 
Follow-up/Final report on designated SAE form 
NON-SERIOUS 
As per eCRF procedure 
Appropriate section of eCRF 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported by the Sponsor 
to all competent Regulatory Authorities, to the Ethics Committees and to all the Investigators 
involved, according to local regulations and requirements stated in ICH Good Clinical 
Practice. 
In the rare event that the Investigator does not become aware of the occurrence of a serious 
adverse event immediately (for example, if an outpatient trial patient initially seeks treatment 
elsewhere), the Investigator has to report the event within 24 hours after learning of it and 
document his/her first awareness of the adverse event. 
Serious adverse events should also be consistently recorded in the appropriate section of e-
CRF. 
Non-serious adverse events have to be reported in the appropriate section of e-CRF only. 
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11.5.1.8. Recording Adverse Events in the Case Report Forms 
Information on AEs must be evaluated by a physician and recorded in source documents such 
as the hospital file. AEs have to be reported in the e-CRF as aforementioned. The Investigator 
will also be asked to assess the relationship between the AE and the investigational 
medication. 
• Preexisting Conditions 
In this trial, a preexisting condition (i.e., a disorder present before the AE reporting period 
started and recorded in the pretreatment medical history form) should not be reported as AE 
unless the condition worsens, or episodes increase in frequency during the AE reporting 
period. 
• Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AE.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as AE and the resulting 
appendectomy should be recorded in the source documents. 
• Symptoms of the Disease 
The specific symptoms of the disease have to be reported as adverse events if they correspond 
to new occurrence or to worsening of severity or frequency versus the baseline visit. 
Note: the general wording “Progression of the disease” should not be reported as adverse 
event. In case of global deterioration of health status requiring discontinuation, further data 
entry instructions are specified in the Study Manual. 
• Abnormal Laboratory Findings 
Abnormal laboratory findings have to be reported as adverse events when they cause study 
drug administration change (dose omission, dose delay, dose reduction, infusion interruption, 
drug discontinuation) or when they require clinical intervention (e.g., hospitalization for 
further investigation or management of the laboratory abnormality). 
 
Note: uncomplicated and asymptomatic abnormal laboratory findings have not to be reported 
as adverse events. The corresponding values have to be reported only in the relevant e-CRF 
section (e.g., hematology, biochemistry). 
11.5.1.9. Grading of Adverse Event Severity 
In this study the severity/intensity of AEs will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE, Version 5.0) of the US National Cancer Institute [21]. 
For each event, changes in severity grade and seriousness criteria should be recorded. 
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For adverse events not reported in the CTCAE Version 5.0, the Investigator will use the Grade 
or adjectives reported in Table 12 
Table 12. Grading of Adverse Event Severity for events  
not reported in the CTCAE v 5.0 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Does not interfere with patient’s usual function 
Grade 2 
Moderate 
Interferes to some extent with patient’s usual function 
Grade 3 
Severe 
Interferes significantly with patient’s usual function 
Grade 4 
Life-threatening 
Results in threatening to life or in an incapacitating disability 
Grade 5 
Death 
Results in death 
Note the distinction between the term “serious” and “severe”, which are not synonymous. The 
term “severe” is used to describe the intensity of a specific event (i.e., severe headache) while 
the term “serious” is based on patient/event outcome or action criteria. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. For example, 
vomiting Grade 1 for which a hospitalization occurred is a serious event even if the event is 
not severe. 
11.5.1.10. Exposure In Utero 
If a female patient becomes or is found to be pregnant while receiving the study drug or within 
180 days from its discontinuation, the Investigator should transmit this information using the 
Part I of Exposure in Utero (EIU) Form to the Sponsor Pharmacovigilance. This must be done 
irrespective of whether an adverse event has occurred and within 24 hours of awareness of 
the pregnancy. However, if the patient begins a new anticancer therapy before 90 days after 
the last dose of study treatment administration, the exposure “in utero” reporting period will 
end at the time the new treatment is started. 
The Investigator will follow the patient until completion of the pregnancy or until pregnancy 
termination (i.e., induced abortion) and then notify the Sponsor of the outcome within 5 days 
or as specified below. The Investigator will provide this information completing Part II of 
EIU form. The reason(s) for an induced abortion must be specified. 
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the Investigator should follow the procedures for 
reporting serious adverse events, i.e., report the event to the Sponsor (as described in Section 
11.5.1.7) 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant must pass before an 
Exposure in Utero Form can be completed). The “normality” of an aborted fetus can be 
assessed by gross visual inspection unless pre-abortion laboratory findings are suggestive of 
a congenital anomaly. 
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Other pregnancy outcomes that are classified as SAEs: 
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality. In addition, any infant death after 1 month that the Investigator assesses as 
possibly related to the “in utero” exposure to the study drug should also be reported. 
If a female partner of a male patient taking the IMP becomes pregnant while the male patient 
is still on IMP or within 90 days after last dose of IMP, the male patient taking IMP should 
notify the Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately. If a pregnancy related event is reported in a female partner 
of a male patient, the Investigator should ask if the female partner is willing to share 
information with the Sponsor and allow the pregnancy related event to be followed up to 
completion.  
The Investigator has to submit the information of pregnancy or suspect pregnancy of a female 
partner of a male patient to the Sponsor Pharmacovigilance by e-mail or by fax, using the EIU 
Form, within 24 hours from his/her awareness of the event. 
11.5.2. Laboratory Safety Assessments 
Laboratory safety assessments will include repeated evaluation of hematology, biochemistry 
and coagulation parameters, urinalyses and pregnancy test, according to timing reported in 
Section 7, Schedule of Events (Table and related footnotes). Investigators may order 
additional blood tests for planning treatment administration, dose modification, or further 
evaluation of adverse events. 
The following laboratory parameters will be used to monitor safety: 
• Hematology (local laboratory) includes: hemoglobin (Hb), red blood cells (RBC), platelet 
(PLT) and white blood cells (WBC) with differential count (neutrophils, lymphocytes, 
monocytes, eosinophils and basophils). The assessment is mandatory, at screening (≤7 
days from treatment start). During treatment on Phase I, hematology should be done from 
cycle 1 to cycle 3, on days 1, 8, 15, 22 and, from cycle 4 onward, on days 1, 8, 15; during 
treatment on Phase II, hematology should be done on cycle 1, on days 1, 8, 15, 22; from 
cycle 2 onward, on days 1, 8, 15; at cycle 2, in case neutropenia Grade ≥2 is observed, 
repeat the hematological evaluation also at day 22. In case of cycle delay due to toxicity 
and/or if clinically indicated, additional assessments should be done as per medical 
judgment; hematology should be repeated at the start of the delayed cycle. All hematology 
assessments performed during the treatment period can be done the day before the 
scheduled one; on days of treatment administration, sampling should be performed and 
results should be available before the start of NMS-01940153E infusion. Hematology 
should be performed also at end of treatment (EoT) and 28-days follow up visits. Note: at 
Cycle 1 Day 1, hematology does not need to be repeated before study drug administration 
if it was performed at screening within 24 hours from treatment start. 
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• Blood chemistry (local laboratory) includes: glucose, electrolytes (Na, K, Ca, P, 
magnesium), urea or BUN (Phase II), serum creatinine, creatinine clearance (calculated 
with Cockroft-Gault equation), total protein, albumin, aspartate aminotransferase 
(AST/SGOT), alanine aminotransferase (ALT/SGPT), gamma-GT, total bilirubin, 
unconjugated bilirubin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH). The 
assessment is mandatory, at screening (≤7 days from treatment start). During treatment on 
Phase I, blood chemistry should be done from cycle 1 to cycle 3, on days 1, 8, 15, 22 and, 
from cycle 4 onward, on days 1, 8, 15; during treatment on Phase II, blood chemistry 
should be done on cycle 1, on days 1, 8, 15, 22 and, from cycle 2 onward, on days 1, 15. 
In case of cycle delay due to toxicity and/or if clinically indicated, additional assessments 
should be done as per medical judgment; blood chemistry should be repeated at the start 
of the delayed cycle. All blood chemistry assessments performed during the treatment 
period can be done the day before the scheduled one; on days of treatment administration, 
sampling should be performed, and results should be available before the start of NMS-
01940153E infusion. Blood chemistry should be performed also at EoT and 28-days 
follow up visits. Note: at Cycle 1 Day 1, blood chemistry does not need to be repeated 
before study drug administration if it was performed at screening within 24 hours from 
treatment start. 
• Coagulation (local laboratory) includes international normalized ratio (INR) of 
prothrombin. The assessment is mandatory, at screening (≤7 days from treatment start). 
During treatment on Phase I, coagulation should be done from cycle 1 to cycle 3, on days 
1, 8, 15, 22 and, from cycle 4 onward, on days 1, 8, 15; during treatment on Phase II, 
blood chemistry should be done on cycle 1, on days 1, 8, 15, 22 and, from cycle 2 onward, 
on days 1, 15. In case of cycle delay due to toxicity and/or if clinically indicated, additional 
assessments should be done as per medical judgment; coagulation should be repeated at 
the start of the delayed cycle. All coagulation assessments performed during the treatment 
period can be done the day before the scheduled one; on days of treatment administration, 
sampling should be performed, and results should be available before the start of NMS-
01940153E infusion. Coagulation should be performed also at EoT and 28-days follow 
up visits. Note: at Cycle 1 Day 1, coagulation does not need to be repeated before study 
drug administration if it was performed at screening within 24 hours from treatment start. 
• Urinalysis (local laboratory) includes: pH, glucose, protein and blood. The assessment is 
mandatory, at screening (≤7 days from treatment start) and at EoT visit. If clinically 
indicated, additional assessments should be done as per medical judgment. 
• Serum/Urine Pregnancy Test (local laboratory). It is indicated only for women of child-
bearing potential. Phase I: the assessment should be done at screening, within 72 hours 
from treatment start, and at EoT visit. Phase II: the assessment should be done at 
screening, within 72 hours from treatment start, on day 1 of each treatment cycle (before 
treatment administration), and at EoT visit. Note: at Cycle 1 Day 1, pregnancy test does 
not need to be repeated before study drug administration if it was performed at screening 
within 24 hours from treatment start. 
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• Serology: in case of positive HBV anamnesis, includes HBV DNA; in case of positive 
HCV anamnesis, includes HCV RNA; in case of HBV unknown anamnesis, includes 
HbsAg, HbeAg, HbcAg, Anti-HBc-IgM; in case of HCV unknown anamnesis, includes 
liver function test as by local standards and HCV Ab. Anti-HIV test. To be performed at 
screening, within 7 days from treatment start. 
In case hematology, blood chemistry and coagulation have not recovered at the end of last 
cycle, they should be followed-up for 28 days after the last study treatment administration or 
until they resolve or the Investigator assesses them as chronic or stable, or until alternative 
anticancer therapy is initiated. In the latest case, the reporting period will end at the time the 
new treatment is started. If the laboratory value is abnormal, clinically significant and 
evaluated as drug related after the 28 days follow-up assessment, it has to be reported only as 
adverse event and as such followed until it resolves or the Investigator assesses it as chronic 
or stable, or until alternative anticancer therapy is initiated. 
11.5.3. Other Safety Assessments 
The following safety assessments will also be performed, according to timing reported in 
Section 7, Schedule of Events: 
• Physical examination: on Phase II should be performed at screening, within 7 days from 
treatment start, on day 1 of each treatment cycle, at EoT and at 28-days follow up. Note: 
at Cycle 1 Day 1, it does not need to be repeated before study drug administration if it was 
performed at screening within 24 hours from treatment start. 
• ECOG PS: should be recorded at screening, within 7 days from treatment start; on day 1 
of each treatment cycle (before treatment administration); at EoT and at 28-days follow 
up visits. Note: at Cycle 1 Day 1, ECOG PS does not need to be repeated before study 
drug administration if it was performed at screening within 24 hours from treatment start. 
• Weight: should be recorded at screening, within 7 days from treatment start, and on day 1 
of each treatment cycle (before treatment administration). 
• Height: should be recorded at screening only. 
• Temperature: should be recorded as Celsius degree, at screening within 7 days from 
treatment start, and on days 1, 8, 15 of each treatment cycle (before treatment 
administration). 
• Blood pressure and heart rate: the assessment is mandatory, at screening within 7 days 
from treatment start; on days 1, 8, 15 before the treatment start and within 30 minutes after 
the end of infusion (before any blood samples is taken); at EoT and 28-days follow up 
visits. At each determination, if SBP >150 mmHg and/or DBP >95 mmHg is registered, 
repeat determinations two more times at 30 minutes interval.  
• Gastro-esophageal endoscopy: should be performed to all patients with known history of 
gastro-esophageal varices. For these patients the assessment is mandatory, at screening 
within 7 days from treatment start, unless an endoscopy is available within 3 months 
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before the treatment start. For all other patients the assessment is not required, granted 
that an endoscopy is available within 24 months before the treatment start, or PI would 
justify the absence of clinical need for this assessment; 
12-lead EC(12-lead, in triplicate, includes qualitative and quantitative assessment): the 
assessment is mandatory at screening, within 7 days from treatment start,  at cycle 1 day 
1 (first dose) and at cycle 1 day 15 (dose 3) triplicate ECG will be collected prior to dosing 
(30 min before the start of infusion and at least 10 minutes after any blood drawn or 
intravenous access procedure) and at peak concentration, prior to and as close as possible 
to the PK timepoint planned 5 minutes before the end of infusion (e.g. ≤ 10 minutes), and 
at EoT visit. It includes QT interval using Fridericia standard (QTcF) calculation. If 
clinically indicated, additional assessments should be done as per medical judgment. To 
be repeated at any time it is medically indicated. If the ECG assessment is not feasible on 
cycle 1 day 1 or cycle 1 day 15, a different timing or other solutions should be discussed 
with Sponsor. At each time point, three consecutive supine 12-lead ECGs will be 
performed approximately 2 minutes apart to determine mean QT interval using Fridericia 
standard (QTcF). The following parameters will be collected: synus rithm, heart rate, RR 
interval, PR interval, QRS interval, QT interval and QTcF interval. For all patients 
enrolled in the study, the Sponsor may request the ECG tracing and reports collected 
during the study be submitted to a third-party for retrospective independent review of the 
ECGs reading and interpretation. 
• AFP: to be performed at screening, within 7 days from treatment start, at the end of even 
cycles at disease evaluation and at EoT. A time window of -2/+5 days is allowed. 
• Survival follow up: the post-treatment survival status, including additional information 
(e.g., new anticancer therapy), will be collected at the 28-days follow up visit and 
thereafter every 2 months from last treatment administration until death. Telephone 
contacts are acceptable for these assessments. 
11.6. Other Assessments 
11.6.1. Blood sampling  
Plasma samples will be used for pharmacokinetic evaluations of NMS-01940153 and its 
main metabolite NMS-03593478. 
During the dose escalation part of the study (Phase I), blood samples will be collected from 
all patients during Cycle 1 and Cycle 2. The sample schema for pharmacokinetic (PK) 
collection is outlined in Table 13. During the Phase II, blood samples will be collected from 
all patients, based on their enrollment number (odd or even), during Cycles 1, 2, 3 and 4. The 
sample schema for PK collection is outlined in Table 14. 
Blood (4 mL/timepoint) will be collected into sodium heparin Vacutainer tubes for PK 
analysis at the designated time. Additional blood samples for PK analysis may be collected 
if, in the opinion of the Investigator and of the Sponsor, an evaluation of PK parameters 
outside the schedule above is needed for safety reasons. 
 
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Table 13. Phase I PK Blood Sample Collection 
Cycle  
Day 
Sample number 
Sample timepoint 
1 
1 
#1 
Pre-dose 
 
 
#2 
5 minutes before the end of infusion 
 
 
#3 
15 minutes after the end of infusion 
 
 
#4 
30 minutes after the end of infusion 
 
 
#5 
1 h after the end of infusion 
 
 
#6 
2 h after the end of infusion 
 
 
#7 
4 h after the end of infusion 
 
 
#8 
6 h after the end of infusion 
 
 
#9 
8 h after the end of infusion 
 
2 
#10 
24 h after the end of infusion 
 
3 
#11 
48 h after the end of infusion 
 
4 
#12 
72 h after the end of infusion 
 
8 
#13 
Pre-dose 
 
15 
#14 
Pre-dose 
 
 
#15 
5 minutes before the end of infusion 
 
 
#16 
15 minutes after the end of infusion 
 
 
#17 
30 minutes after the end of infusion 
 
 
#18 
1 h after the end of infusion 
 
 
#19 
2 h after the end of infusion 
 
 
#20 
4 h after the end of infusion 
 
 
#21 
6 h after the end of infusion 
 
 
#22 
8 h after the end of infusion 
 
16 
#23 
24 h after the end of infusion 
 
17 
#24 
48 h after the end of infusion 
 
18 
#25 
72 h after the end of infusion 
 
22 
#26 
168 h after the end of infusion 
2 
1 
#27 
Pre-dose 
 
8 
#28 
Pre-dose 
 
15 
#29 
Pre-dose 
On Phase I, during Cycle 1, the total volume of blood withdrawn for pharmacokinetic 
determinations from each patient will be 104 mL over 22 days (26 samples); during Cycle 2, 
the total volume of blood withdrawn for pharmacokinetics determinations from each patient 
will be 12 mL over 15 days (3 samples). 
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Table 14. Phase II PK Blood Sample Collection 
Cycle  
Day 
Sample 
number 
Enrollment 
number 
Sample timepoint 
1 
1 
201 
All 
5 minutes before the end of infusion 
 
 
202 
Odd 
From 15 min to 2h after the end of infusion 
 
 
203 
Even 
From >2h to 6h after the end of infusion 
 
8 
204 
Odd 
Pre-dose 
 
 
205 
Even 
5 minutes before the end of infusion 
 
15 
206 
All 
Pre-dose 
 
 
207 
All 
5 minutes before the end of infusion 
 
 
208 
Even 
From 15 min to 2h after the end of infusion 
 
 
209 
Odd 
From >2h to 6h after the end of infusion 
 
22 
210 
All 
At any time 
2 
1 
211 
All 
Pre-dose 
 
15 
212 
All 
Pre-dose 
 
 
213 
All 
5 minutes before the end of infusion 
 
 
214 
Odd 
From 15 min to 2h after the end of infusion 
 
 
215 
Even 
From >2h to 6h after the end of infusion 
 
26 or 27 or 28 
216 
All 
At any time 
3 
15 
217 
All 
Pre-dose 
 
 
218 
All 
5 minutes before the end of infusion 
 
 
219 
Even 
From 15 min to 2h after the end of infusion 
 
 
220 
Odd 
From >2h to 6h after the end of infusion 
4 
1 
221 
All 
Pre-dose 
 
15 
222 
All 
Pre-dose 
 
 
223 
All 
5 minutes before the end of infusion 
 
 
224 
Odd 
From 15 min to 2h after the end of infusion 
 
 
225 
Even 
From >2h to 6h after the end of infusion 
 
26 or 27 or 28 
226 
All 
At any time 
 
On Phase II, during Cycle 1, the total volume of blood withdrawn for PK determinations from 
each patient will be 28 mL over 22 days (7 samples); during Cycle 2, the total volume of 
blood withdrawn for PK determinations from each patient will be 16 mL over 26/28 days (4 
samples); during Cycle 3, the total volume of blood withdrawn for PK determinations from 
each patient will be 12 mL over 1 day (day 15; 3 samples); during Cycle 4, the total volume 
of blood withdrawn for PK determinations from each patient will be 16 mL over 26/28 days 
(4 samples).  
Details on PK samples collection, processing, storage and shipping instructions will be 
provided in the Study Manual. 
11.6.2.1. Bioanalytical method  
NMS-01940153E and its main metabolite NMS-03593478 will be assayed in plasma using a 
validated LC-MS/MS method. Pharmacokinetics analysis will be performed by Accelera S.r.l. 
(located in Italy) identified by the Sponsor as the entity in charge of samples shipment, storage 
and analysis. 
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11.6.3. Urine Sampling 
Urine samples will be used for determination of the urinary excretion of the parent drug and 
its main metabolite. 
Urine samples will be collected only during the phase I of the study, at Cycle 1, on days 1 and 
15. Urine will be collected before NMS-01940153E administration and in four different 
portions between 0-6h, 6-24h, 24-48h, 48-72h from the start of study drug administration. 
At the end of the urine collection period, for each portion, the total volume of urine will be 
measured, and total volume recorded in eCRF. The urine will then be mixed aliquots 
withdrawn for PK analysis, as outlined in Table 15. 
Table 15. PK Urine Sample Collection 
Cycle 
Day 
Sample number 
Sample timepoint 
1 
1 
#1 
Pre-dose 
 
 
#2 
0-6h from the start of infusion 
 
 
#3 
6-24h from the start of infusion 
 
 
#4 
24-48h from the start of infusion 
 
 
#5 
48-72h from the start of infusion 
 
15 
#6 
Pre-dose 
 
 
#7 
0-6h from the start of infusion 
 
 
#8 
6-24h from the start of infusion 
 
 
#9 
24-48h from the start of infusion 
 
 
#10 
48-72h from the start of infusion 
Additional urine samples for PK analysis may be collected if, in the opinion of the Investigator 
and of the Sponsor, an evaluation of PK parameters outside the schedule above is needed for 
safety reasons. 
Details on sample collection and handling and shipping instructions will be provided in the 
Study Manual. 
All the samples for pharmacokinetic determinations will be sent to Accelera (located in Italy), 
or other identified by the Sponsor as the entity in charge of samples shipment, storage and 
analysis. 
11.6.4. Exploratory Assessments 
11.6.4.1. cfDNA Sampling 
For cfDNA analysis, 20 ml of peripheral blood will be collected for all patients at screening. 
Sponsor might decide, at any time, to stop collection of these samples based on scientific or 
logistic reasons. 
 
 
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12. STATISTICAL METHODS 
12.1. Sample Size Calculation 
An overall sample size of approximately 55 patients may be anticipated considering both 
phases of the study. 
For the Phase I, approximately 12-15 treated patients may be expected. Since the trial design 
foresees that sequential dose-escalation steps are applied to cohorts of 3 to 6 patients up to the 
identification of the MTD, the number of patients who will be enrolled and treated may vary, 
depending upon the toxicity observed that will influence cohort size and number of dose levels 
tested. 
For the Phase II, the investigator-assessed objective response rate by RECIST 1.1. will be the 
primary outcome measure.  
The sample size is based on precision considerations for the estimate of the primary efficacy 
endpoint. A single-group design will be used to obtain a one-sided 95% lower-limit 
confidence interval for a single proportion. The sample proportion is assumed to be 0.3. To 
produce a confidence interval with a distance from the sample proportion to the lower limit 
of no more than 0.12, 38 patients will be needed. A lower bound of 18% for ORR by RECIST 
would be meaningful relative to second line therapies in HCC.  The emergence of 
atezolizumab with bevacizumab in first line has obscured true current second line outcomes 
with regorafenib, lenvatinib or sorafenib but it is logical to assume second line ORR would 
be no better relative to the pre-atezolizumab/bevacizumab era in which sorafenib was the first 
line standard.  Prior to the atezolizumab/bevacizumab era, regorafenib in second line showed 
ORR of 11% by RECIST1.1 [10] and cabozantinib 4% [22], nivolumab 15% [23], 
pembrolizumab 18% [24] and apatinib 10.7% [25].  Therefore, in the third line setting 
following failure of atezolizumab/bevacizumab in first line followed by TKI in second line, 
and where current third line standards are not yet defined,  it is reasonable to expect historical 
ORR no higher than 18%. Accounting for a 10% proportion of non-evaluable patients and if 
the stopping rule for futility is not met, up to 43 patients could be required for completing the 
trial, as reported in detail in Section 12.4;  however, the Phase II part of the study will not 
enroll beyond 40 subjects unless discussed and agreed with FDA or relevant health authority, 
based on emerging response rates. 
12.2. Definition of Analyzed Study Populations 
The following analysis sets are defined according to ICH E9 guidelines [26]. 
Phase I Dose Escalation 
Enrolled Set (ES): this population will include all patients who are enrolled in Phase I part, 
regardless of whether patients receive study treatment or not. This population will be 
evaluated in the analysis of patients’ disposition. 
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Treated Set (TS): this set will include all enrolled patients who take at least one dose of NMS-
01940153E. This population will be evaluated in the analysis of patients’ disposition, baseline 
characteristics, treatment exposure, safety and efficacy. 
Dose-Limiting Toxicity Evaluable Set (DLTES): this set will include all patients who receive 
in the first cycle at least 66% of study drug, unless the reason for non-compliance is drug-
related toxicity, and undergo a DLT assessment within the DLT window. Patients not 
fulfilling one or more of aforementioned criteria will not be considered evaluable for MTD 
determination and will be substituted.  
Phase II 
Enrolled Set (ES): this population will include all patients enrolled in Phase II, regardless of 
whether patients receive study treatment or not. This population will be evaluated in the 
analysis of patients’ disposition. 
Treated Set (TS): this set will include all enrolled patients who actually receive at least one 
dose of NMS 01940153E. This population will be evaluated in the analysis of patients’ 
disposition, baseline characteristics, treatment exposure and safety. 
Evaluable Set (ES): this is the patient population for the primary efficacy analysis. This set 
will include patients of the TS who have measurable disease at baseline assessed according to 
RECIST 1.1 and at least one tumor evaluation on treatment, unless they die before the first 
tumor on-treatment assessment, in which case they will be considered treatment failure. 
In detail, the evaluable population for primary efficacy endpoint will consist of a subset of the 
evaluable population up to the total number of subjects pre-determined by the interim for 
futility and final analyses. This means that, if the number of evaluable subjects exceeds the 
planned total number of subjects at either stage, the exceeding subjects will not be considered 
for primary efficacy analysis. Subjects will be counted into the primary evaluable population, 
consecutively, based on the date of first NMS-01940153E administration. 
12.3. Analyses 
A Statistical Analysis Plan [26] will be written and completed before the planned interim 
analysis and locking the Database. These specifications will detail the implementation of all 
the planned statistical analyses in accordance with the principal features stated in the 
following sections. 
Patients from the Phase I part and from the Phase II part will be analyzed separately. 
12.3.1. Study Conduct and Subject Disposition 
Patients’ disposition and reasons for ending the treatment and the study will be presented in 
frequency distribution tables and individual data listings. The patients not meeting the 
eligibility criteria, and who are considered protocol violators will be identified and described 
by individual data listing. Reasons for stopping treatment will be summarized as frequency 
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distribution in the treated patient population and, if clinically interesting, in other patient 
subsets. Untreated patients will be identified and described separately. 
12.3.2. Baseline Characteristics and Treatment Group Comparability 
Descriptive statistics of the baseline characteristics will be generated across all treated patients 
and, if clinically interesting, in other patient subsets. Frequency distributions will be presented 
for the categorical/categorized variables. Summary statistics including mean, standard 
deviation, median, minimum, maximum and the number of assessed patients will be 
calculated, as appropriate, for the quantitative variables. Individual data will be presented in 
listings. 
The study has no comparative arm. 
12.3.3. Treatment Administration/Compliance 
The treatment exposure and the compliance with study treatment will be descriptively 
analyzed in the treated patient population and, if clinically interesting, in other patient subsets. 
Descriptive statistics (e.g. min, max, mean, standard deviation, and median value) will be 
calculated on a per-patient basis for the following variables: the number of cycles 
administered, the overall duration of treatment, the actual and total doses administered, and 
the absolute and relative dose intensity. Frequency distributions of patients and/or cycles will 
be used to describe dose modifications, delays and omissions, as well as the reasons for 
deviation from the planned therapy. Individual data will be presented in listings as reported 
in the relevant CRF sections. 
12.3.4. Efficacy Analyses 
The efficacy of NMS-01940153E will be assessed on the treated set for Phase I and evaluable 
set for Phase II, respectively, as defined in Section 12.2. For Phase II, only if deemed of 
interest and only as supportive analysis, efficacy could be also evaluated on the treated 
population. 
12.3.4.1. Primary Efficacy Endpoint 
For Phase II part, the primary efficacy endpoint ORR will be evaluated as the proportion of 
patients who have achieved as best overall response, CR or PR as defined by investigator-
assessed RECIST 1.1. In addition to the point estimate, binomial exact confidence intervals 
will be provided. 
The decision rules for interim analysis for futility are specified in Section 12.1. 
12.3.4.2. Secondary Efficacy Endpoints 
Objective response rate will be also calculated for Phase II part only, as the percentage of 
evaluable patients with best response equal to complete response (CR) or partial response 
(PR) as defined by investigator-assessed mRECIST. Binomial exact confidence intervals will 
be also provided. 
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Time-to-event endpoints, i.e. Duration of Response (DoR), Progression Free Survival and 
Overall Survival: they will be carried out on treated set for Phase I and evaluable set for Phase 
II, respectively. Time-to-event endpoints will be also summarized using Kaplan Meier (KM) 
curves and further characterized in terms of median and landmark estimates with the 
corresponding confidence intervals, for Phase II part only. 
12.3.5. Outcomes Research Analyses 
Not applicable 
12.3.6. Safety Analyses 
Unless otherwise specified, the safety analyses will be performed on the treated set by 
assigned dose level and overall for Phase I and overall for Phase II. 
Adverse events will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
and their severity will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE, version 5.0). The analysis will focus on the events reported after 
the start of treatment (treatment emergent adverse events). For each dose level and overall, 
the incidence of AEs will be grouped by System Organ Class (SOC) and by preferred term. 
Each patient will be counted once according to the worst grade reported throughout the whole 
treatment period for each SOC and/or for each preferred term. If clinically indicated, selected 
AEs will be presented by treatment cycle (Cycle 1 vs. Cycles >1). In addition, SAEs, AEs 
with severity grade 3-5, AEs leading to treatment withdrawal and AEs related to study 
treatment, will be reported separately. 
The DLT occurrence during the first treatment cycle will be reported for the Dose-Limiting 
Toxicity Evaluable Set (DLTES). 
Frequency of deaths will be presented overall and by dose level, by relationship to the study 
treatment and according to the time since treatment discontinuation. 
Laboratory data will be graded according to the NCI CTCAE scale (version 5.0) whenever 
possible. Laboratory abnormalities will be summarized in frequency distribution tables by 
dose level and treatment period (i.e. treatment Cycle 1, Cycle >1 and the whole treatment 
period). For each parameter, patients will be classified based on the maximal severity grade 
observed during the analyzed time-window. Changes of severity grade vs. baseline will be 
evaluated by shift tables. Selected laboratory parameters will be further explored by analyzing 
the nadir/zenith values, the time to nadir/zenith and the time to recovery after nadir/zenith, as 
clinically indicated. 
For the laboratory data not graded by the NCI CTCAE scale, a cross tabulation of on treatment 
worst finding versus baseline finding will be presented reporting the number of patients with 
values within or out of the normal range. 
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All collected safety data (including vital signs, ECG, laboratory assessments and adverse 
events, etc.) will be presented in individual patients’ data listings. Identification of clinically 
relevant values and calculation of changes from baseline will be provided for those parameters 
and conditions deemed of clinical relevance. 
12.3.7. Analyses of Other Endpoints 
12.3.7.1. Alpha-Fetoprotein as Surrogate Marker of Efficacy 
Exploratory analysis on the relationship between AFP levels and treatment efficacy variables 
in patients treated with NMS-01940153E will be performed if sufficient data are collected. 
12.3.7.2. Pharmacokinetic 
12.3.7.2.1. Phase I Dose Escalation 
The pharmacokinetics of NMS-01940153E and its metabolite NMS-03593478 in plasma and 
urine will be assessed by standard non-compartmental analysis using Phoenix WinNonlin 8.1 
or later version (Certara Company). 
The following pharmacokinetic parameters will be provided on both Day 1 and Day 15: 
maximum concentration (Cmax) and related time of achievement (Tmax), last detectable 
concentration (Clast) and related time of observation (Tlast), area under concentration versus 
time up to 168 hours (dosing interval), half-life of the terminal phase (t½,z), plasma clearance 
(CL), volume of distribution (Vss) and renal clearance (CLR). 
On Day 1, for NMS-01940153E and NMS-03593478, maximum concentration, Cmax,D1, 
and related time of achievement, Tmax,D1, last detectable concentration, Clast,D1, and 
related time of observation, Tlast,D1, will be taken directly from the raw data. 
Area under concentration versus time up to the last detectable concentration (AUClast) will 
be calculated using the linear trapezoidal rule. The half-life of the terminal phase, t½,z, will 
be determined by linear regression analysis of the natural-log concentration versus time 
curve according to the formula: 
z
,
2
/
1
)
2
ln(

=
z
t
 
where z is the slope of the regression line. A minimum of three data points will be used in 
calculating z. 
AUC∞ (D1) will be calculated by adding the portion of the area calculated as 
z
D1
last, / 
C
 to 
AUClast,D1.  
The clearance (CL) of NMS-01940153E will be calculated according to the formula: 
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D1
AUC
Dose
 
CL

=
 
The volume of distribution at steady state (Vss) of NMS-01940153E will be calculated 
according to the formula: 
MRT
CL
Vss

=
, where 
2
inf
1
1
t
AUC
AUMC
MRT
D
D −
=
 
On Day 15, Cmax,D15, Tmax,D15, Clast,D15 and Tlast,D15 will be taken directly from the 
raw data. 
AUC0-168,D15, AUClast,D15 and AUCD15 will be calculated as on Day 1. 
The clearance (CL) of NMS-01940153E will be calculated according to the formula: 
D15
 ,
AUC
Dose
 
CL

=
 
where AUCτ is the area under the curve in the dosing interval. 
Accumulation ratios for NMS-01940153E and NMS-03593478, based on Cmax (RA,Cmax) and 
AUClast (RA,AUClast) will be calculated as the ratio between the individual parameter obtained 
on Day 15 to the corresponding one on Day 1. 
On Day 1 and Day 15, metabolite to parent ratio will be calculated based on Cmax and AUClast 
values. 
On Day 1 and Day 15, the amount of NMS-01940153E and its metabolite NMS-03593478 
excreted in urine in the time interval 0-72 h (Ae0-72) will be calculated multiplying the urinary 
concentration by the urinary volume in the collection times: 0-6, 6-24, 24-48 and 48-72 hours.  
The parameter will be also expressed as percent of dose (fe%). For the metabolite, the 
parameter expressed as percent of dose will be calculated after correction of the dose for the 
molecular weight of the compound. 
Renal clearance of NMS-01940153E and its metabolite NMS-03593478 will be calculated as: 
CLR = Ae0-72 / AUC0-72 
Statistical analysis 
Descriptive statistics (mean SD, CV%, min, max, median) will be calculated for plasma and 
urine concentration data and pharmacokinetic parameters. 
Statistical analysis will be performed after a log-transformation of the data of NMS-
01940153E treatment. For each group separately, a mixed effect model will be fitted with day 
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as fixed effect and subject as a random effect. Day 15 will be compared to Day 1 for each 
dose level. The ratio will be calculated by back-transforming the difference between the Least 
Square means. Using the estimate of variance, 90 % confidence intervals will be calculated 
for the difference and back-transformed. Results of the analyses will be reported in the 
paragraph of the statistical results. 
The power method will be used to evaluate the dose proportionality of NMS-01940153E and 
possibly its metabolite. Cmax, AUClast, AUC0-168 and AUC data on Day 1 and Day 15. Dose 
versus Cmax and AUCs relationship will be performed using the power model 
y = a  Doseb 
This relationship becomes linear after a logarithmic transformation 
log(y) = log(a) + b  log(dose) 
where a is the intercept to y (AUC) axis and b is the slope of the regression line. Dose 
proportionality required slope to be close to unity for dose dependent parameters, and decision 
on dose proportionality will be made based on the inclusion of the theoretical slope of 1 in the 
90 % confidence intervals. 
12.3.7.2.2. Phase II 
For PK plasma samples collected during Phase II, a sparse sampling procedure will be 
adopted. For each patient, a total of 20 plasma samples will be collected; the blood sample 
intervals are designed to patients to grant homogeneous distribution of the samplings in 
different time intervals (refer to Table 14). 
Pharmacokinetic data from Phase II portion of the study will be analyzed using mixed-effect 
modeling approach. Data may be also pooled with PK data from previous Phase I studies. 
Details of the sampling procedures as well as population PK model development description 
and population PK data analysis will be detailed in the population PK Statistical Analysis 
Plan. 
The objective of the population pharmacokinetic data analysis will be to describe the 
pharmacokinetics of NMS-01940153E in the subject population and explore the role of 
demographic and pathophysiological covariates influencing the pharmacokinetics of the 
compound. The main pharmacokinetic parameters and the influence of covariates (e.g., 
gender, age, body weight, histopathological covariates) will be estimated using a population 
PK approach. The key guidances of FDA and EMA will be followed in the population PK 
analysis. The population PK analysis will be performed using NONMEM software (version 
VII or higher). 
The population PK model will consist of the following: 
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• identification of the structural model that best describe the pharmacokinetic data in 
absence of covariates. 
• Identification of the variance component/s characterizing between-patient variability 
(BSV) in model parameters. The between-patient variability (BSV) will be modeled as an 
exponential random-effect model in order to positively constrain the individual parameter 
values, which will be thus assumed to follow the following log-normal distribution:  
 
( )
i
Typical
i



exp

=
 
where θi is the PK parameter for the ith individual, θTypical is the typical value (geometric 
mean) of the parameter in the population, ηi is a random inter-patient effect with mean 0 
and estimated variance ω2. 
• Residual unexplained variability will be modeled using additive or proportional or 
additive and proportional models, or other error models considered suitable. The residual 
error i,j will be assumed to be normally distributed with mean 0 and the variance 2. 
12.3.7.2.3. Covariate Analysis 
Covariate analysis will be performed using visual inspection in order to identify relevant 
covariates explaining the variability of NMS-01940153E. The most relevant covariates will 
be then formally evaluated using a stepwise forward additive approach using a p-value of 0.05 
and a backward elimination using a p-value of 0.01 (chi-squared distribution). 
12.3.7.3. Translational Research 
Exploratory analyses on biomarkers in blood and tumor will be conducted based on the 
completeness of data collected. 
12.4. Interim Analysis Plan 
In the Phase II part of the study an interim evaluation for futility will be undertaken as soon 
as the first 10 evaluable patients will be enrolled and the data for primary efficacy endpoint 
analysis will be available including observations through at least 3 months with at least 1 
on-treatment tumor assessment by RECIST 1.1. If less than 1 responder i.e., patients who 
achieved CR or PR as best overall response, are observed, the study will be terminated for 
futility. This futility decision must be taken before 20 subjects total are enrolled otherwise 
enrollment will pause at 20 subjects until non-futility can be declared (if applicable).  If at 
least 1 unconfirmed or confirmed responder is observed and there are no safety limitations, 
patients’ enrollment will continue and proceed up to an overall enrollment of 38 evaluable 
patients or 40 total patients. For the safety monitoring, if two or more patients on study 
experience Grade 4 adverse events the study will be put on hold to evaluate whether to 
continue or if additional risk mitigation is warranted.  The independent DSMB will review 
the interim results and provide a recommendation on the study progress. 
Notification of the temporarily interruption of recruitment as well as restart of enrollment will 
be notified to the IECs. 
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12.5. Data Monitoring Committee 
An independent DSMB will provide study oversight through periodic safety evaluations and 
make recommendations on study progress in the transition from Phase I to Phase II and at the 
planned interim analysis for the futility of Phase II. 
During the Phase I part, teleconferences will be held at the end of each cohort between the 
Investigators and the Sponsor to review all relevant safety and PK data and take decision on 
the dose escalation to be applied to the next cohort of patients. Once the MTD is identified, 
and the safety profile of NMS-01940153E has been reviewed by the Investigators, the Sponsor 
and the independent DSMB and is considered adequate based on the Phase I data available, 
the RP2D will be defined and the Phase II portion of the study will start.  
Two clinical experts in the field of hepatology or onco-hepatology and a statistician, who are 
not involved in the study and have no conflict of interest with respect to study results, will 
compose the independent DSMB. 
Tasks of the independent DSMB will be: 
• To provide a recommendation on study progress in the transition from Phase I to Phase 
II and at the planned interim analysis for the futility of Phase II, based on risk-benefit 
evaluation; 
• To periodically review adverse events, serious adverse events and all other safety and 
pharmacokinetic data collected during the study;  
• To suggest other toxicities to be recorded/monitored in the group of patients who will be 
enrolled after the independent DSMB safety evaluation. 
 
13. END OF THE TRIAL 
For the purpose of this study, the end of the trial is defined as the date of the last visit of the 
last patient, including follow up. 
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14.  QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
The Investigator must permit study-related monitoring, audits performed by the Sponsor or 
designee, IRB/IEC review, and regulatory agency inspections and provide direct access to 
source data documents. 
It is important that the Investigator and his/her relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.  
The Sponsor or designee is responsible for the data management of the study including quality 
checking of the data. That means that following data entry or electronic receipt of data, data 
validation will take place and Forms/Reports for data clarifications will be addressed to the 
Investigator. Data management activities will address the coding and review of terms by 
scientific and clinically qualified staff. 
15. DATA HANDLING AND RECORD KEEPING 
15.1. Electronic Case Report Forms (eCRFs) 
An eCRF must be filled in by the Investigator or authorized delegate for each enrolled and 
treated patient. Refer to Study Manual data entry instructions about data required for patients 
classified as screening failure or enrolled but untreated. 
It is the Investigator’s or authorized delegate’s responsibility to ensure completion and to 
review and authorize release of the eCRF for each enrolled Clinical Trial Patient. The 
signature on the eCRF serves to attest that the information contained in the eCRF is true, 
accurate and reliable. At all times, the Investigator has full responsibility for the accuracy, 
legibility, completeness, and timeliness of all data (e.g., clinical data, laboratory results) 
reported in the eCRF and in the related data clarification tools (e.g., Data Clarification, 
Discrepancy Notes, Queries). 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigational Site. Source 
documents would include, but are not limited to, hospital/clinic records, physicians’ and 
nurses’ notes, appointment books, original laboratory result reports, ECG, x-rays, signed 
informed consent forms (ICF). 
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15.2. Record Retention 
Any study records and documents, including signed ICFs, pertaining to the conduct of the 
study, must be retained by the Investigator for the period of time specified in the Clinical Trial 
Agreement, unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
15.3. Confidentiality of Clinical Trial or Study Documents 
All documents and information given to the Investigator by the Sponsor with respect to NMS-
01940153E and study MPSA-153-001 are strictly confidential. 
The Investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this Clinical Trial, for carrying out the Clinical Trial Protocol. This 
agreement is binding as long as the confidential information has not been disclosed to the 
public by the Sponsor. 
The Investigator must not disclose any information of Clinical Trial Protocol as well as any 
information extracted from it to other parties without the prior written authorization of the 
Sponsor. The only exception is upon request of the representatives of the Competent 
Authorities; in the latter case, the Investigator commits himself to informing the Sponsor prior 
to disclosure of information to these authorities. 
16. ETHICS 
16.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Clinical Study Protocol, Protocol Amendments, Informed Consent Forms, Investigator 
Brochure and other relevant documents (e.g., advertisements) must be submitted to 
IRB(s)/IEC(s) by the Investigator(s) and/or Sponsor/Delegate Party in accordance with local 
regulations reviewed and approved by the IRB(s)/IEC(s) before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. In that case, the Investigator must notify the IRB/IEC, the 
Sponsor or Delegated Party and Regulatory Authority, as applicable, as soon as possible after 
the implementation. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
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• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
16.2. Ethical Conduct of the Trial 
This study will be conducted in accordance with and with the following: 
• The Clinical Trial Protocol 
• Ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines. 
• Current and applicable laws and regulations. 
The Investigator will be responsible for: 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies, as applicable, and all other applicable local regulations. 
16.3. Informed Consent Process 
It is the responsibility of the Investigator (or a person designated by the Investigator when 
accepted by local regulations) to give each individual (or his/her legally authorized 
representative) full and adequate explanation regarding the nature of the study (e.g., 
objectives, aims, methods and procedures of the study, anticipated benefits, possible risks and 
potential hazards involved). The Investigator or his/her delegate will answer all questions 
regarding the study.  
Participants must be informed that their participation is voluntary and that they have the right 
to withdraw from the study at any time. 
Participants or their legally authorized representative will be required to sign before any trial-
related procedure is undertaken, a statement of informed consent (ICF) that meets the 
requirements of ICH guidelines, 21 CFR 50 and Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, local regulations, and the 
IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
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A copy of the signed ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
16.4. Personal Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or designee will contain the identifier only; 
participant names or any information which would make the participant identifiable will not 
be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor or designee in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor or 
designee, by appropriate IRB/IEC members, and by inspectors from Regulatory Authorities. 
17. SPONSOR DISCONTINUATION CRITERIA 
Nerviano Medical Sciences reserves the right to discontinue the trial prior to inclusion of the 
intended number of patients but intends only to exercise this right for valid scientific or 
administrative reasons. After such a decision, the Investigator must contact all participating 
patients. As directed by Nerviano Medical Sciences or the Delegated Party, all study materials 
must be collected and all case report forms completed to the greatest extent possible. 
18. DISSEMINATION AND PUBLICATION OF RESULTS 
Results of the study may be presented or published. The conditions regulating dissemination 
of the information derived from this clinical study are described in the Clinical Trial 
Agreement. 
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19. REFERENCES 
1. 
https://seer.cancer.gov/statfacts/html/livibd.html 
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Forner A, Reig M, Bruix J. Hepatocellular Carcinoma. Lancet. 2018 Mar; 391:1301-
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https://www.registri-
tumori.it/cms/sites/default/files/pubblicazioni/2018_NumeriCancro-operatori.pdf 
4. 
El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. 
Gastroenterology. 2012 May; 142(6):1264-1273. 
5. 
Llovet JM, Brú C, Bruix J. Prognosis of Hepatocellular Carcinoma: The BCLC Staging 
Classification. Semin Liver Dis. 1999; 19(3):329-38. 
6. 
Wörns MA, Galle PR. Hepatocellular carcinoma in 2017: Two large steps forward, one 
small step back. Nat Rev Gastroenterol Hepatol. 2018; 15(2):74-76. 
7. 
Piscaglia F, Ogasawara S. Patient selection for transarterial chemoembolization in 
hepatocellular carcinoma: importance of benefit risk assessment. Liver Cancer. 2018 
Mar; 7(1):104–19. 
8. 
Rimassa L, Pressiani T, Merle P. Systemic Treatment Options in Hepatocellular 
Carcinoma. Liver Cancer 2019; 8:427–446. 
9. 
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro 
A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle 
PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, 
Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular 
carcinoma. N Engl J Med. 2008 Jul; 359(4):378–390 
10. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, 
Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-
Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, 
Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with 
hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a  
andomized, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2017 Jan; 389 
(10064):56-66. 
11. Finn RS, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc 
O, Gerolami R, Caparello C, Cabrera R, Chang C, Sun W, LeBerre MA, Baumhauer A, 
Meinhardt G, Bruix J. Outcomes of sequential treatment with sorafenib followed by 
regorafenib for HCC: additional analyses from the phase III RESORCE trial. J Hepatol. 
2018 Aug; 69(2):353–358. 
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12. Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: Looking outside the box. 
J. Hepatol. 2020; 72:342–352. 
13. NCCN Guidelines HCC: 
 
https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf 
14. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, 
Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, 
Lim HY, Zhu AX, Cheng AL. Atezolizumab plus Bevacizumab in Unresectable 
Hepatocellular Carcinoma. N Engl J Med. 2020; 382:1894-905. 
15. Investigator's Brochure NMS-01940153E (S81694), Version n° 8 August 2021. 
16. Phase I dose-escalation study of S 81694 administered intravenously in adult patients 
with advanced/metastatic solid tumors. Abbreviated Clinical study report, 17 Mar 2020. 
17. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuckh S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Eur. J. Cancer. 2009; 45 (228-247). 
18. American Joint Committee on Cancer (AJCC): TNM Staging for Hepatocellular Cancer. 
8th ed., 2017 
19. Reig M et al. BCLC strategy for prognosis prediction and treatment recommendation: 
The 2022 update. J Hepatol 2022;76:681-693 
20. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for Hepatocellular 
Carcinoma Semin Liver Dis 2010 Feb;30(1):52-60 
21. Common Terminology Criteria for Adverse Events (CTCAE) (cancer.gov) 
22. G.K. Abou‑Alfa, T. Meyer, A.-L. Cheng, A.B. El‑Khoueiry, L. Rimassa, B.-Y. Ryoo, 
I. Cicin, P. Merle, Y.H. Chen, J.-W. Park, J.-F. Blanc, L. Bolondi, H.-J. Klümpen, S.L. 
Chan, V. Zagonel, T. Pressiani, M.-H. Ryu, A.P. Venook, C. Hessel, A.E. 
Borgman‑Hagey, G. Schwab, and R.K. Kelley  Cabozantinib in patients with advanced 
and progressing hepatocellular carcinoma. N Engl J Med 2018; 379:54-63. 
23. Yau T , Hsu C, Kim TY, Choo SP, Kang YK, Hou M-M, Numata K, Yeo W, Chopra A, 
Ikeda M, Kuromatsu R, Moriguchi M, Chao Y, Zhao H, Anderson J, Dela Cruz C, Kudo 
M. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian 
cohort analysis. J. Hepatol. 2019; 71:543–552. 
24. Merle P, Edeline J, Bouattour M, Cheng AL, Lam Chan S, Yau T, Garrido M,. Knox JJ, 
Daniele B, Zhu AX, Vladimirovich Breder V, Lim HY, Ogasawara S, Siegel AB, 
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Rahman A, Wei Z, Finn RS. Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) 
with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: 
Updated data from the randomized, phase III KEYNOTE-240 study. J Clin Oncol 39, 
no. 3_suppl (January 20, 2021) 268-268 
25. Li Q, Qin S, Gu S, Chen X, Lin L, Wang Z, Xu A, Chen X, Zhou C, Ren Z, Yang L, Xu 
L, Bai Y, Chen L, Li J, Pan H, Cao B, Fang W, Yan P, Jin C. Apatinib as second-line 
therapy in Chinese patients with advanced hepatocellular carcinoma: A randomized, 
placebo-controlled, double-blind, phase III study. J Clin Oncol 38, no. 15_suppl (May 
20, 2020) 4507-4507. 
26. ICH Topic E9 – Statistical Principles for Clinical Trials: Published in the Federal 
Register, September 1998, Vol. 63, No. 179, p. 49583; Adopted by CPMP, March 1998, 
issued as CPMP/ICH/363/96/Step 5. 
27. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
FDA Web site 
28. http://dbts.ucsf.edu/fdatransportal 
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APPENDICES 
 
Appendix 1. ECOG Performance Status 
Grade ECOG Performance Status 
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 
 
 
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Appendix 2. Child Pugh Score and Classification 
 
Child Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, mol/l (mg/dl) <34 (<2) 34-50 (2-3) 
>50(>3) 
Serum albumin, g/dl 
>3.5 
2.8-3.5 
<2.8 
PT INR 
<1.7 
1.70-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to severe 
Hepatic encephalopathy 
None 
Grade I-II 
(or suppressed with 
medication) 
Grade III-IV (or 
refractory) 
 
Chronic liver disease is classified into Child_Pugh class A to C, employing the added score 
from above. 
Child-Pugh Classification 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
 
Child CG, Turcotte JG. Surgery and portal hypertension. In: The liver and portal hypertension. Edited by CG 
Child. Philadelphia: Saunders 1964:50-64. 
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus in bleeding 
oesophageal varices. Br J Surg 1973;60:648-52. 
 
 
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Appendix 3. Contra-indicated drugs 
 
The following lists are not intended to be exhaustive lists [27-28]. For updated interaction 
information please refer to drug summary of product characteristics. Investigators should 
verify case by case. 
No strong inducers of FMO1 and FMO3 are currently known; they are contraindicated as a 
theoretical rule. 
Sensitive CYP3A4 substrates 
 
CYP3A4 
Sensitive substrates* 
Alfentanil, Avanafil, Budesonide, Buspirone,  Conivaptan, Darifenacin, Darunavir, 
Dasatinib Dronedarone, Ebastine, Eletriptan, Eplerenone, Everolimus, Felodipine, 
Ibrutinib, Indinavir, Lomitapide, Lovastatin, Lurasidone, Maraviroc, Midazolam, 
Naloxegol, Nisoldipine, Quetiapine,Saquinavir, Sildenafil, Simvastatin, Sirolimus, 
Tacrolimus, Ticagrelor, Tipranavir, Tolvaptan, Triazolam, Vardenafil 
* Substrates metabolized at least at 80% by CYP3A4 
 
CYP3A 
Substrates with NTI 
Alfentanil**, Astemizole, Cisapride, Cyclosporine, Dihydroergotamine, 
Fentanyl, Pimozide, Quinidine, Sirolimus**, Tacrolimus**, Terfenadine. 
** also sensitive CYP3A4 substrates 
 
No BCRP substrates with NTI are currently known; they are contraindicated as a theoretical 
rule. 
 
 
FDA, Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 
 
 
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Appendix 4. Concomitant treatments to be used with caution 
 
The following lists are not intended to be exhaustive lists [27-28]. For updated interaction 
information please refer to drug summary of product characteristics. Investigators should 
verify case by case. 
No strong inhibitors of FMO1 and FMO3 are currently known. 
 
Moderate sensitive CYP3A4 substrates 
 
CYP3A 
Moderate substrates* 
Alprazolam, Aprepitant, Atorvastatin, Colchicine, Eliglustat, Rilpivirine, 
Rivaroxaban, Tadalafil 
* Substrates metabolized from 50% to 80% by CYP3A4. 
 
BCRP  
Substrates with no NTI 
Atorvastatin, 
Hematoporphyrin, 
Imatinib, 
Pitavastatine, 
Rosuvastatin, 
Sofosbuvir, Sulfasalazine, Tizanidine 
 
 
FDA, Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 
 
 
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Appendix 5. The Distribution of Active Bone Marrow in the Adult 
Site 
Marrow 
Weight (g) 
Fraction Red 
Marrow - Age 40 
Red Marrow 
Weight -Age 40 (g) 
% Total Red 
Marrow 
Head 
 
 
136.6 
13.1 
Cranium 
165.8 
0.75 
124.3 
 
Mandible 
16.4 
0.75 
12.3 
 
Upper Limb Girdle 
 
 
86.7 
8.3 
2 Humerus, head & neck 
26.5 
0.75 
20.0 
 
2 Scapulae 
67.4 
0.75 
50.5 
 
2 Clavicles 
21.6 
0.75 
16.2 
 
Sternum 
39.0 
0.6 
23.4 
2.3 
Ribs 
 
 
82.6 
7.9 
1 pair 
10.2 
All 0.4 
4.1 
 
2 
12.6 
 
5.0 
 
3 
16.0 
 
6.4 
 
4 
18.6 
 
7.4 
 
5 
23.8 
 
9.5 
 
6 
23.6 
 
9.4 
 
7 
25.0 
 
10.0 
 
8 
24.0 
 
9.6 
 
9 
21.2 
 
8.5 
 
10 
16.0 
 
6.4 
 
11 
11.2 
 
4.5 
 
12 
4.6 
 
1.8 
 
Vertebrae  (Cervical) 
 
 
35.8 
3.4 
1 
6.6 
All 0.75 
5.0 
 
2 
8.4 
 
6.3 
 
3 
5.4 
 
4.1 
 
4 
5.7 
 
4.3 
 
5 
5.8 
 
4.4 
 
6 
7.0 
 
5.3 
 
7 
8.5 
 
6.4 
 
Vertebrae (Thoracic) 
 
 
147.9 
14.1 
1 pair 
10.8 
All 0.75 
8.1 
 
2 
11.7 
 
8.8 
 
3 
11.4 
 
8.5 
 
4 
12.2 
 
9.1 
 
5 
13.4 
 
10.1 
 
6 
15.3 
 
11.5 
 
7 
16.1 
 
12.1 
 
8 
18.5 
 
13.9 
 
9 
19.7 
 
14.8 
 
10 
21.2 
 
15.9 
 
11 
21.7 
 
16.3 
 
12 
25.0 
 
18.8 
 
Vertebrae (Lumbar) 
 
 
114.1 
10.9 
1 pair 
27.8 
All 0.75 
20.8 
 
2 
29.1 
 
21.8 
 
3 
31.8 
 
23.8 
 
4 
32.1 
 
24.1 
 
5 
31.4 
 
23.6 
 
Sacrum 
194.0 
0.75 
145.6 
13.9 
Lower limb girdle 
 
 
273.0 
26.1 
2 os coxae 
310.6 
0.75 
233.0 
 
2 femoral head & neck 
53.0 
0.75 
40.0 
 
Total 
1497.7 
 
1045.7 
100.0 
R.E. ELLIS - The Distribution of Active Bone Marrow in the Adult. Phy. Med. Biol. 5, 255 – 258, 1961. 
 
 
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Appendix 6. Recommended Effective Contraception 
Since NMS-01940153E has potential induction of CYP3A4, hormonal contraceptives might 
lose efficacy while on treatment with NMS-01940153E and therefore this should specially 
be taken into account for female patients. It is advisable, unless total abstinence is applied, 
to use two contraceptive methods, of which at least one barrier method. 
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods and therefore 
recommended. Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:  
− oral  
− intravaginal  
− transdermal  
• progestogen-only hormonal contraception associated with inhibition of ovulation:  
− oral  
− injectable  
− implantable  
• intrauterine device (IUD)   
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• vasectomy 
• sexual abstinence   
 
In case of male patients who have not had a vasectomy, the partner with a childbearing 
potential should use one of the highly effective contraceptive methods reported above. 
 
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SAP_003.pdf: 
Document Type:  
Final Statistical Analysis Plan 
Document Date:  
30 June 2023 
Study Title:  
Study on Safety and Efficacy of NMS-01940153E in Adult Patients 
With Unresectable Hepatocellular Carcinoma (HCC) Previously 
Treated With Systemic Therapy  
Protocol Reference Number:  MPSA-153-001  
NCT Number:  
NCT05630937 


 
 
MPSA-153-001/Statistical Analysis Plan/Final V.2/30-Jun-2023 
 
 
Statistical Analysis Plan 
 
 
ENSURE TO USE THE CURRENT VERSION OF THIS TEMPLATE AVAILABLE ON THE INTRANET 
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Page 1 of 26 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
Protocol Title 
Phase I/II study on safety and efficacy of NMS-01940153E in 
adult patients with unresectable hepatocellular carcinoma 
(HCC) previously treated with systemic therapy  
 
 
Investigational 
Medicinal Product(s) 
Code /Name 
NMS-01940153E  
 
 
Development Phase 
Phase I/II 
 
 
 
Protocol Number 
MPSA-153-001 
 
 
Protocol Version and 
Date  
Version 5.0, 9-Jan-2023 
 
 
 
SAP Version Number 
2.0 
 
 
SAP Date 
30-Jun-2023 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ......................................................................................................... 4 
2. 
PURPOSE OF THE STATISTICAL ANALYSIS PLAN ................................................................ 6 
2.1. 
CHANGES TO PREVIOUS VERSION .................................................................................................... 6 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................... 7 
3.1. 
OBJECTIVES ................................................................................................................................... 7 
3.1.1. 
Primary Objective(s) ....................................................................................................................... 7 
3.1.2. 
Secondary Objective(s) .................................................................................................................. 7 
3.1.3. 
Exploratory Objective(s) ................................................................................................................ 7 
3.2. 
ENDPOINTS ..................................................................................................................................... 8 
3.2.1. 
Primary Endpoint(s) ........................................................................................................................ 8 
3.2.2. 
Secondary Endpoint(s) ................................................................................................................... 8 
3.2.3. 
Exploratory Endpoint(s) ................................................................................................................. 8 
4. 
STUDY DESIGN ........................................................................................................................... 8 
4.1. 
OVERVIEW ...................................................................................................................................... 8 
4.2. 
SUBJECT SELECTION....................................................................................................................... 9 
4.3. 
SAMPLE SIZE ................................................................................................................................ 10 
4.4. 
TREATMENT ALLOCATION (AND BLINDING) ..................................................................................... 10 
5. 
OVERVIEW OF PLANNED ANALYSES .................................................................................... 11 
5.1. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) / INDEPENDENT DATA SAFETY MONITORING 
BOARD (DSMB) ........................................................................................................................... 11 
5.2. 
PLANNED SCHEDULE OF INTERIM ANALYSES .................................................................................. 11 
5.3. 
FINAL ANALYSES AND REPORTING ................................................................................................. 12 
6. 
CHANGES IN THE PLANNED ANALYSIS ................................................................................ 12 
7. 
ANALYSIS POPULATIONS ....................................................................................................... 12 
8. 
GENERAL SPECIFICATIONS FOR STATISTICAL ANALYSES ............................................. 13 
8.1. 
HANDLING MISSING DATA.............................................................................................................. 14 
8.2. 
ANALYSIS CONVENTIONS ............................................................................................................... 14 
8.3. 
ANALYSIS SOFTWARE ................................................................................................................... 14 
9. 
STATISTICAL ANALYSES ........................................................................................................ 14 
9.1. 
PATIENT DISPOSITION ................................................................................................................... 14 
9.2. 
PROTOCOL DEVIATIONS ................................................................................................................ 15 
9.3. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ............................................................ 15 
9.4. 
PREVIOUS OR CONCOMITANT MEDICATIONS/ PROCEDURES ............................................................ 15 
9.5. 
NEW ANTICANCER THERAPIES / PROCEDURES ............................................................................... 15 
9.6. 
TREATMENT EXPOSURE AND COMPLIANCE ..................................................................................... 16 
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9.7. 
EFFICACY ANALYSES .................................................................................................................... 16 
9.7.1. 
Primary Efficacy Endpoint(s) ...................................................................................................... 16 
9.7.2. 
Secondary Efficacy Endpoint(s) ................................................................................................ 16 
9.8. 
SAFETY ANALYSES ....................................................................................................................... 17 
9.8.1. 
Treatment Emergent Adverse Events ....................................................................................... 17 
9.8.2. 
Dose Limiting Toxicities .............................................................................................................. 18 
9.8.3. 
Deaths ............................................................................................................................................... 19 
9.8.4. 
Clinical Laboratory Evaluations ................................................................................................. 19 
9.8.5. 
Other Safety Evaluations (e.g. Vital signs, ECG, ECOG PS, etc.) ..................................... 20 
9.9. 
EXPLORATORY ANALYSES ............................................................................................................. 21 
10. 
REFERENCES ............................................................................................................................ 22 
11. 
APPENDICES ............................................................................................................................. 24 
12. 
APPROVAL AND SIGNATURES ............................................................................................... 25 
13. 
VERSION HISTORY ................................................................................................................... 26 
 
 
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1. LIST OF ABBREVIATIONS  
 
AE 
Adverse Event 
AFP 
Alpha-Fetoprotein 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
cfDNA 
Circulating Free DNA 
CI 
Confidence Interval 
Cmax 
Maximum plasma Concentration 
CR 
Complete Response 
CSR 
Clinical Study Report 
CT 
Clinical Trial 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Scan 
Computerized tomography scanner 
DBP 
Diastolic Blood Pressure 
DLT 
Dose Limiting Toxicity 
DLTES 
Dose Limiting Toxicity Evaluable Set 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
eCRF 
electronic Case Report Form 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ES 
Enrolled Set 
FIH 
First in Human 
(𝛾) −GT 
Gamma - Glutamyl Transferase 
HCC 
Hepatocellular Carcinoma 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
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LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
MeDRA 
Medical Dictionary for Regulatory Activities 
MPS1 
Monopolar Spindle 1 kinase 
MTD 
Maximum Tolerated Dose  
MRI 
Magnetic Resonance Imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
OR 
Overall Response 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease (unless otherwise specified in the text) 
PK 
Pharmacokinetic 
PFS 
Progression Free Survival 
PR 
Partial Response (unless otherwise specified in the text) 
QTc 
Corrected Fridericia QT Interval 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Dose Recommended for further Phase II investigations 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation (unless otherwise specified in the text)  
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TLG 
Table Listing and Graph 
TKI 
Tyrosine kinase Inhibitor 
TTK 
Tyrosine/Threonine Kinase 
TS 
Treated Set 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
 
 
 
 
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2. PURPOSE OF THE STATISTICAL ANALYSIS PLAN 
This Statistical Analysis Plan (SAP) version 2.0, describes the planned Phase I analysis, Phase II 
interim and final analyses and reporting for MPSA-153-001 Clinical Trial (CT).  All analyses take 
origin from the specifications in the statistical section of the CT Protocol version 5.0 (9-Jan-2023). 
Details of changes of the SAP version 2.0 respect to the first version, created based on CT Protocol 
version 2.0 dated 28-Jan-2021, are reported in Section 2.1.  
Of note, this SAP does not cover the pharmacokinetic (PK) data analyses, described in the 
Protocol. These analyses are covered in a separate document written by Accelera S.r.l. 
The structure and content of this SAP provide sufficient detail to guarantee compliance with the 
requirements identified by the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): E9 Guidance on 
Statistical Principles in Clinical Trials and Integrated Addendum to E9(R1) [1].  
The planned analyses identified in this SAP may be included in future abstracts, presentations and 
manuscripts, and may also support other documents, e.g. Development Safety Update Report 
(DSUR). Exploratory analyses not necessarily identified in this SAP may be performed to support 
planned analyses. Any post-hoc or unplanned analyses not specified in this SAP will be clearly 
identified as such in the Clinical Study Report (CSR). 
The following documents were reviewed when preparing this SAP:  
• 
CT Protocol version 5.0 (09-Jan-2023)  
• 
CT Specific Case report forms (CRFs) Blank version 5.3 (23-Jun-2023)  
• 
E9 - Statistical Principles for Clinical Trials [Integrated Addendum to E9(R1)] [1]  
• 
E6(R2) - Guidance on Good Clinical Practice [Integrated Addendum to E6(R1)] [1] 
• 
E3 - Guidance on Structure and Content of Clinical Study Reports [1] 
• 
Applicable NMS procedural documents 
2.1. Changes to Previous Version 
The following changes are made in the current version 2.0 of the SAP: 
- 
SAP re-written using new template (version T1_02, 17-May-2023). The mock-ups of tables, 
listings and graphs and algorithms are provided as separated Appendix using a new 
template (version T2_02, 17-May-2023). 
- 
Section 3 Study Objectives and Endpoints was modified based on updated definition of 
primary efficacy objective and endpoint for Phase II and inclusion of additional secondary 
and exploratory endpoints. 
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- 
Section 4 Study Design, specifically Overview, Subject Selection and Sample Size, was  
modified based on the updated Phase II design. 
- 
Section 5.2 Planned Schedule for Interim Analyses was modified based on the updated 
Phase II design that includes also a safety monitoring rule. 
- 
Section 7, was updated to add clarifications for the definition of Evaluable Set for Phase II 
portion based on protocol version 5.0. 
- 
Section 8 General Specification for Statistical Analysis, was mainly updated to include 
secondary phase II efficacy endopoints based on mRECIST evaluation. 
- 
Section 9.7 Efficacy Analyses and Sections 9.7.1 Primary Efficacy Endpoint and 9.7.2 
Secondary Efficacy Endpoints, were updated.  
- 
Section 9.8.5 was updated to include additional ECG parameters collected for patients 
enrolled in Phase II. 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1. Objectives 
3.1.1. Primary Objective(s) 
• 
To determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) 
of NMS-01940153E administered as single agent to adult patients with unresectable 
hepatocellular carcinoma (HCC) previously treated with systemic therapy (Phase I). 
• 
To assess the anti-tumor efficacy of NMS-01940153E administered as single agent to adult 
patients with unresectable hepatocellular carcinoma previously treated with systemic therapy 
(Phase II). 
3.1.2. Secondary Objective(s) 
• 
To define the safety and tolerability profile of NMS-01940153E. 
• 
To evaluate the pharmacokinetics of NMS-01940153E and its main metabolite NMS-
03593478 in plasma and, limited to Phase I, also in urine. 
• 
To evaluate additional measures of antitumor efficacy of NMS-01940153E. 
3.1.3. Exploratory Objective(s) 
• 
To explore correlation among Alpha-Fetoprotein (AFP) levels changes with NMS-01940153E 
exposure and clinical outcomes. 
• 
To explore correlation among baseline tumoral and clinical prognostic factors with clinical 
outcome. 
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• 
To explore the potential correlation of selected molecular alterations in circulating free DNA 
(cfDNA) at baseline with clinical outcome. 
3.2. Endpoints 
3.2.1. Primary Endpoint(s) 
• 
Drug related Dose Limiting Toxicities (DLTs) (Phase I). 
• 
Objective Response Rate (ORR). The ORR will be calculated as the proportion of evaluable 
patients who have achieved, as best overall response (BOR), confirmed complete response 
(CR) or partial response (PR) measured by investigator-assessed RECIST 1.1 (Phase II). 
3.2.2. Secondary Endpoint(s) 
• 
Overall safety profile of NMS-01940153E characterized by type, severity (graded using NCI 
CTCAE Version 5.0), duration of the adverse events (AEs) and laboratory and ECG 
abnormalities, and relationship of the AEs to study treatment in the first and subsequent cycles 
of therapy. 
• 
Pharmacokinetic parameters of NMS-01940153E and its main metabolite NMS-03593478 in 
plasma and urine (urine only in Phase I). 
• 
Objective Tumor Response (Partial and Complete Response) as measured by investigator-
assessed RECIST 1.1 (Phase I). 
• 
Objective response rate as measured by investigator-assessed mRECIST (Phase II). 
• 
Duration of response (DoR) as measured by investigator-assessed RECIST 1.1. and 
investigator-assessed mRECIST. 
• 
Progression Free Survival (PFS), including landmark analyses, as measured by investigator-
assessed RECIST 1.1. 
• 
Overall survival (OS). 
3.2.3. Exploratory Endpoint(s) 
• 
Evaluation of AFP plasma levels. 
• 
Evaluation of tumoral and other clinical prognostic features at baseline. 
• 
Assessment of selected molecular alterations in circulating free DNA (cfDNA) at baseline. 
 
4. STUDY DESIGN 
4.1. Overview  
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This is a Phase I/II, open-label, non-randomized, multicenter study to explore safety, tolerability 
and antitumor activity of NMS-01940153E as single agent in adult patients with unresectable HCC 
previously treated with systemic therapy.  
An independent Data Safety Monitoring Board (DSMB) will provide study oversight through 
periodic safety evaluations and make recommendations on study progress in the transition from 
Phase I to Phase II and at the planned interim analysis for the futility of Phase II. 
The Phase I portion is designed as a dose-escalation study in sequential cohorts of patients aimed 
to obtain the MTD that is defined based on the DLTs observed in the first cycle of treatment.  
The safety profile of NMS-01940153E administered IV on days 1, 8, 15 every 4 weeks has been 
characterized in the FIH, dose escalation study, conducted in adult patients with 
advanced/metastatic solid tumors up to the dose of 135 mg/m2/week. This dose was not defined 
as MTD in study 2014-002023-10 (EudraCT), since only one patient experienced DLT (Grade 3 
fatigue) out of 6 evaluable patients. 
Once the MTD is identified and the safety profile of NMS-01940153E has been reviewed by the 
Investigators, the Sponsor and the independent DSMB and is considered adequate based on the 
entire Phase I data available, the Phase II portion of the study will start. 
The Phase II portion is designed as a two-stage study with an interim analysis for futility and 
stopping criteria for unacceptable toxicity to assess the antitumor activity of NMS-01940153E in 
adult patients with unresectable HCC previously treated with systemic therapy measured as 
objective response rate. In the Phase II portion, patients will receive the RP2D defined in the Phase 
I portion of the  study as starting dose. Patients will be enrolled in continuous, and continuously 
evaluated for endpoints, with a futility analysis and stopping criteria for unacceptable toxicity 
performed as described in Section 5.2. The enrollment will be stopped in the event of futility as 
described in Section 5.2, with no more than 20 subjects treated overall until non-futility can be 
declared, if appropriate. In any case, the Sponsor may stop or pause enrollments any time during 
the study based on safety, efficacy or strategic reasons. 
4.2. Subject Selection 
This is a Phase I/II study in adult patients (>=18 years) with unresectable HCC, disease relapsed 
or refractory to the standard of care treatment not exceeding 3 lines of prior systemic treatment. 
For the Phase I portion subjects intolerant to previous treatment with tyrosine kinase inhibitors 
(TKIs) are eligible. 
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For the Phase II portion  subjects must have disease relapsed or refractory to the standard of care 
treatment including an immunocheckpoint inhibitor as first line and at least a TKI, with no more 
than 3 prior lines of systemic therapies. 
4.3. Sample Size 
An overall sample size of approximately 55 patients may be anticipated considering both 
phases of the study. 
For the Phase I, approximately 12-15 treated patients may be expected. Since the trial design 
foresees that sequential dose-escalation steps are applied to cohorts of 3 to 6 patients up to the 
identification of the MTD, the number of patients who will be enrolled and treated may vary, 
depending upon the toxicity observed that will influence cohort size and number of dose levels 
tested. 
For the Phase II, the investigator-assessed objective response rate by RECIST 1.1. [2] will be the 
primary outcome measure.The sample size is based on precision considerations for the estimate 
of the primary efficacy endpoint. A single-group design will be used to obtain a one-sided 95% 
lower-limit confidence interval for a single proportion. The sample proportion is assumed to be 0.3. 
To produce a confidence interval with a distance from the sample proportion to the lower limit of 
no more than 0.12, 38 patients will be needed. A lower bound of 18% for ORR by RECIST would 
be meaningful relative to second line therapies in HCC. The emergence of atezolizumab with 
bevacizumab in first line has obscured true current second line outcomes with regorafenib, 
lenvatinib or sorafenib but it is logical to assume second line ORR would be no better relative to 
the pre-atezolizumab/bevacizumab era in which sorafenib was the first line standard. Prior to the 
atezolizumab/bevacizumab era, regorafenib in second line showed ORR of 11% by RECIST1.1 [3] 
and cabozantinib 4% [4], nivolumab 15% [5], pembrolizumab 18% [6] and apatinib 10.7% [7]. 
Therefore, in the third line setting following failure of atezolizumab/bevacizumab in first line 
followed by TKI in second line, and where current third line standards are not yet defined, it is 
reasonable to expect historical ORR no higher than 18%. Accounting for a 10% proportion of non-
evaluable patients and if the stopping rule for futility is not met, up to 43 patients could be required 
for completing the trial, as reported in detail in Section 5.2; however, the Phase II part of the study 
will not enroll beyond 40 subjects unless discussed and agreed with FDA or relevant health 
authority, based on emerging response rates. 
4.4. Treatment Allocation (and Blinding) 
Not applicable 
 
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5. OVERVIEW OF PLANNED ANALYSES 
5.1. Independent Data Monitoring Committee (IDMC) / Independent Data Safety Monitoring 
Board (DSMB) 
 
An independent DSMB will provide study oversight through periodic safety evaluations and make 
recommendations on study progress in the transition from Phase I to Phase II and at the planned 
interim analysis for the futility of Phase II. 
During the Phase I part, teleconferences will be held at the end of each cohort between the 
Investigators and the Sponsor to review all relevant safety and PK data and take decision on the 
dose escalation to be applied to the next cohort of patients. Once the MTD is identified, and the 
safety profile of NMS-01940153E has been reviewed by the Investigators, the Sponsor and the 
independent DSMB and is considered adequate based on the Phase I data available, the RP2D 
will be defined and the Phase II portion of the study will start. 
Two clinical experts in the field of hepatology or onco-hepatology and a statistician, who are not 
involved in the study and have no conflict of interest with respect to study results, will compose the 
independent DSMB. 
Tasks of the independent DSMB will be: 
• 
To provide a recommendation on study progress in the transition from Phase I to Phase II 
and at the planned interim analysis for the futility of Phase II, based on risk-benefit 
evaluation; 
• 
To periodically review adverse events, serious adverse events and all other safety and 
pharmacokinetic data collected during the study; 
• 
To suggest other toxicities to be recorded/monitored in the group of patients who will be 
enrolled after the independent DSMB safety evaluation. 
5.2. Planned Schedule of Interim Analyses 
In the Phase II part of the study an interim evaluation for futility will be undertaken as soon as the 
first 10 evaluable patients will be enrolled and the data for primary efficacy endpoint analysis will 
be available including observations through at least 3 months with at least 1 on treatment tumor 
assessment by RECIST 1.1 [2]. If less than 1 responder i.e., patients who achieved CR or PR as 
best overall response, are observed, the study will be terminated for futility. This futility decision 
must be taken before 20 subjects total are enrolled otherwise enrollment will pause at 20 subjects 
until non-futility can be declared (if applicable). If at least 1 unconfirmed or confirmed responder is 
observed and there are no safety limitations, patients’ enrollment will continue and proceed up to 
an overall enrollment of 38 evaluable patients or 40 total patients. For the safety monitoring, if two 
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or more patients on study experience Grade 4 adverse events the study will be put on hold to 
evaluate whether to continue or if additional risk mitigation is warranted.The independent DSMB 
will review the interim results and provide a recommendation on the study progress.  
5.3. Final Analyses and Reporting 
All final planned analyses identified in the protocol and in this SAP will be performed only after the 
last patient has completed the last visit scheduled, including follow-up and the clinical database 
has been cleaned and locked. 
The mock-ups tables, listings and graphs for reporting purpose of CT MPSA-153-001 are reported 
in the separate appendix “Tables, Listings and Graphs Mock-ups and Algorithms”. 
6. CHANGES IN THE PLANNED ANALYSIS 
 Not applicable 
 
7. ANALYSIS POPULATIONS 
Phase I Dose Escalation 
Enrolled Set (ES): this population will include all patients who are enrolled in Phase I part, 
regardless of whether patients receive study treatment or not. This population will be evaluated in 
the analysis of patients’ disposition. 
Treated Set (TS): this set will include all enrolled patients who take at least one dose of NMS- 
01940153E. This population will be evaluated in the analysis of patients’ disposition, baseline 
characteristics, treatment exposure, safety and efficacy. 
Dose-Limiting Toxicity Evaluable Set (DLTES): this set will include all patients who receive in the 
first cycle at least 66% of study drug, unless the reason for non-compliance is drug-related toxicity, 
and undergo a DLT assessment within the DLT window. Patients not fulfilling one or more of 
aforementioned criteria will not be considered evaluable for MTD determination and will be 
substituted. 
Phase II Part 
Enrolled Set (ES): this population will include all patients enrolled in Phase II, regardless of 
whether patients receive study treatment or not. This population will be evaluated in the analysis 
of patients’ disposition. 
Treated Set (TS): this set will include all enrolled patients who actually receive at least one dose 
of NMS 01940153E. This population will be evaluated in the analysis of patients’ disposition, 
baseline characteristics, treatment exposure and safety. 
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Evaluable Set (ES): this is the patient population for the primary efficacy analysis. This set will 
include patients of the TS who have measurable disease at baseline assessed according to 
RECIST 1.1 and at least one tumor evaluation on treatment, unless they die before the first 
tumor on-treatment assessment ( i.e. if the patients died within 61 days from the start of the 
treatment considering that the first on treatment tumor assessment is forseen at the end of cycle 
2 with a time window of  -2/+5 days), in which case they will be considered treatment failure. 
Moreover, subjects must have disease relapsed or refractory to the standard of care treatment 
including an immunocheckpoint inhibitor as first line and at least a tyrosine kinase inhibitor, not 
exceeding 3 lines of prior systemic treatment. Patients who received the RP2D defined in phase I 
portion as starting dose and from cycle 2 a dose increment of 25% (as per protocol version 4.0 
dated 30-Jun-2022) were considered not evaluable for efficacy analysis (intra-patient dose 
escalation no more applicable as per protocol version 5.0).  In detail, the evaluable population for 
primary efficacy endpoint will consist of a subset of the evaluable population up to the total 
number of subjects pre-determined by the interim for futility and final analyses. This means that, 
if the number of evaluable subjects exceeds the planned total number of subjects at either stage, 
the exceeding subjects will not be considered for primary efficacy analysis. Subjects will be 
counted into the primary evaluable population, consecutively, based on the date of first NMS-
01940153E administration. 
8. GENERAL SPECIFICATIONS FOR STATISTICAL ANALYSES 
This section provides a general overview of the methods to analyze the study data. Specific 
analyses will be reported in the appropriate section 9.   
Continuous (quantitative) variables will be summarized using descriptive statistics including 
number of non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Selected continuous variables will also be described in classes (e.g. age, QTc, etc.) 
Frequency and percentage will be provided for categorical variables and generated for parameter 
estimates of interest. In general, the denominator for the percentage calculation will be based upon 
the number of treated patients, unless otherwise indicated, by dose level and overall in the study 
population.  
For the efficacy analyisis, the percentage of the ORR, according to the RECIST 1.1 [2] or mRECIST 
[8], will be reported both as a point estimate and by means of 95% CIs . 
The survival curve and the quartiles (25th percentile, median, 75th percentile) will be estimated for 
the time-to-event endpoints (i.e. DoR, PFS and OS) using the Kaplan-Meier method [9] and will be 
reported along with the corresponding 95% Confidence Intervals (CIs). Reverse Kaplan-Meier 
method [10] will be used to estimate the median length of follow-up for PFS and OS. 
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8.1. Handling Missing Data 
Specific information for imputing missing data, where appropriate, will be documented in the 
separate appendix TLGs Mock-ups and Algorithms. Except for time related endpoints, missing 
observations will not be imputed, unless otherwise noted.  
8.2. Analysis Conventions 
All collected data will be presented in listings. Data not subject to analyses according to this plan 
will not appear in any tables or graphics but will be included only in the data listings.  
Partial dates in principle will not be imputed except for date of birth. Only year of birth will be 
collected in the database and to estimate patient’s age, December 31st will be used to replace the 
missing month and day, respectively. 
Censoring rules for time-to-event endpoints are reported in the appendix TLGs Mock-ups and 
Algorithms, provided as a separate document. 
Study day will be calculated in reference to the date of first study treatment dose. For assessments 
conducted on or after the first dose, study day is calculated as (assessment date – first dose date 
+1). For assessments conducted before the first dose, study day is calculated as (assessment date 
– first dose date). The study day will be displayed in all relevant data listings.  
The baseline visit will correspond to the last assessment with non-missing result performed before 
initial study drug administration, unless otherwise indicated in the appendix TLGs Mock-ups and 
Algorithms. 
All analysis conventions are detailed in the separate appendix TLGs Mock-ups and Algorithms. 
8.3. Analysis Software 
Data processing, data listings, tabulation of descriptive statistics, calculation of inferential statistics 
and graphical representations will be performed using SAS® Software (release 9.4 or higher) for 
Windows, unless otherwise specified. 
9. STATISTICAL ANALYSES 
9.1. Patient Disposition 
Patients’ disposition and reasons for ending the treatment and the study will be presented in 
frequency distribution tables and individual data listings by study phase and dose level. The 
patients not meeting the eligibility criteria, and who are considered protocol violators will be 
identified and described by individual data listing by study phase. Reasons for stopping treatment 
will be summarized as frequency distribution in the treated patient population. Untreated patients 
will be identified and described separately. 
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9.2. Protocol Deviations 
Protocol deviations will be classified as critical, major or minor based on MPSA-153-001 Protocol 
Deviations classification document. The patients not meeting the eligibility criteria, and who are 
considered protocol violators as well as patients excluded from efficacy analysis, will be identified 
and described by individual data listings.  
Protocol deviations that will exclude patients from analysis populations are defined in section 7. 
9.3. Demographics and Other Baseline Characteristics 
Demographic information, disease history, medical history, prior antitumor therapies/ procedures 
for enrolled patients, will be provided as listings. 
Descriptive statistics for demographic data will be generated for both enrolled and treated patients 
by study phase. Other baseline characteristics such as history of current and other tumors, relevant 
medical history, previous antitumor treatments and procedures, and vital signs will be generated 
across all treated patients by study phase.  
The baseline assessment corresponds to the last non-missing analysis performed before initial 
study drug administration, unless otherwise indicated in in the appendix TLGs Mock-ups and 
Algorithms. 
Frequency distributions will be presented for the categorical/categorized variables (e.g. sex, ECOG 
PS and race). Summary statistics including mean, standard deviation, median, minimum, 
maximum and the number of assessed patients will be calculated, as appropriate, for the 
quantitative variables (e.g. age, weight, systolic and diastolic blood pressure).  
The continuous data, such as age, will also be described in classes.  
9.4. Previous or Concomitant Medications/ Procedures 
Previous or concomitant medications/procedures will be descriptively analyzed in the treated 
patient population by dose level and by Study Phase, and reported in data listings. Previous or 
concomitant medications will be coded by World Health Organization Drug (WHODrug) Global B3 
dictionary [11]. The frequency and percentage of all previous or concomitant medications will be 
summarized by preferred term. Patients will only be counted once within preferred term. Previous 
or concomitant procedures/radiotherapy will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA) and the number and percentage of subjects with previous or  concomitant 
procedures/radiotherapy will be summarized by MedDRA preferred term [12].  
9.5. New Anticancer Therapies / Procedures 
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No other approved or investigational anticancer treatment will be permitted during the study 
treatment period, including chemotherapy, immunotherapy, biological response modifiers, and 
hormones. 
New antitumor systemic therapies, new radiotherapies and new procedures after discontinuation 
of study treatment will be provided respectively in a data listing.  
9.6. Treatment Exposure and Compliance  
For each study phase, the treatment exposure and the compliance with study treatment will be 
descriptively analyzed in the treated patient population. Descriptive statistics (e.g. min, max, mean, 
standard deviation, and median value) will be calculated on a per-patient basis for the following 
variables: the number of cycles administered, the overall duration of treatment, the actual and total 
doses administered, and the absolute and relative dose intensity. Frequency distributions of 
patients and/or cycles will be used to describe dose modifications such as dose delayed, dose 
increased, dose omitted, infusion slowed, infusion interrupted and cycle delayed or in advance, as 
well as the reasons for deviation from the planned therapy. Individual data will be presented in 
listings as reported in the relevant CRF sections. 
9.7. Efficacy Analyses 
The efficacy of NMS-01940153E will be assessed on the treated set for Phase I and evaluable set 
for Phase II, respectively, as defined in Section 7. For Phase II, only if deemed of interest and only 
as supportive analysis, efficacy could be also evaluated on the treated population. 
Event dates, censoring definitions for time-to-event efficacy endpoints and other specific definitions 
are provided in the separate appendix TLGs Mock-ups and Algorithms. 
9.7.1. Primary Efficacy Endpoint(s) 
For Phase II part, the primary efficacy endpoint ORR will be evaluated as the proportion of patients 
who have achieved as best overall response, CR or PR as defined by investigator assessed 
RECIST 1.1. In addition to the point estimate, binomial exact 95% confidence intervals will be 
provided. 
The decision rules for interim analysis for futility are specified in Section 5.2. 
9.7.2. Secondary Efficacy Endpoint(s) 
For the Phase I part, the objective tumor response (Partial and Complete response) will be reported 
in patients’ data listings. 
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ORR  will be also calculated for Phase II part only, as the percentage of evaluable patients with 
best response equal to complete response (CR) or partial response (PR) as defined by 
investigator-assessed mRECIST. Binomial exact 95% confidence intervals will be also provided. 
Time-to-event endpoints (i.e. DoR, PFS and OS): they will be carried out on treated set for Phase 
I and evaluable set for Phase II, respectively. The individual calculated times will be presented in 
patients’ data listings together with the identification of censored vs. failure status. Time-to-event 
endpoints will be also summarized using Kaplan Meier (KM) curves and further characterized in 
terms of median, 6-month, 9-month and 12-month estimates with the corresponding 95% 
confidence intervals, for Phase II part only. 
Reverse Kaplan-Meier method [9] will be used to estimate length of follow-up for DoR, PFS and 
OS by reversing censored and event observations, if applicable.  
9.8. Safety Analyses 
Unless otherwise indicated, all safety analyses will be performed on the treated patient population 
by study phase and dose level. All collected safety data (adverse events, laboratory assessments, 
vital signs, ECG parameters, concomitant medications etc.), will be presented in individual patients’ 
data listings. 
9.8.1. Treatment Emergent Adverse Events 
Adverse events (AEs) will be coded by Medical Dictionary for Regulatory Activities (MedDRA) and 
their severity will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0) [13]. The analysis will focus on the events emerged during treatment and on 
those worsened on treatment in comparison to the baseline condition (TEAE, treatment emergent 
adverse events). For each dose level and overall, the incidence of AEs will be grouped by System 
Organ Class (SOC) and preferred term or by preferred term only. Each patient will be counted 
once according to the worst grade reported throughout the whole treatment period for each SOC 
and/or for each preferred term. 
AEs will be summarized by descending frequency of SOC and preferred term, or preferred term 
only, depending of the analysis reported, unless otherwise specified. In addition, serious AEs, AEs 
with severity grade 3-5, AEs leading to treatment withdrawal, AEs leading to treatment reduction, 
omission, delay, infusion interrupted, infusion rate slowed, and AEs related to study treatment, will 
be analysed separately. A summary table of number and percentage of each possible AE 
categories (e.g. all AE, related AEs, serious, serious related etc.) will be also provided. 
The analysis of number of occurrences of non-serious AEs, serious AEs, serious related to NMS-
01940153E AEs and serious AEs leading to death by SOC and preferred term will be performed 
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only for regulatory purpose since these data have to be recorded in EudraCT/Clingov databases 
at end of the trial. This analysis will be only reported as appendix in the CSR.   
9.8.2. Dose Limiting Toxicities 
A DLT will be defined as any of the adverse events described in MPSA-153-001 Clinical Protocol 
Section 5.2.1 occurring in Cycle 1, during Phase I dose escalation, for which the relationship to 
NMS-01940153E cannot be definitely excluded. Toxicities are to be graded according to the NCI 
CTCAE version 5.0 [13]. In particular: 
Hematological Toxicity 
• 
Neutropenia Grade 4 lasting >7 days or Grade 4 of any duration associated with Grade ≥2 
infection 
• 
Febrile neutropenia ANC <1000/mm3 and a single temperature of >38.3 degrees C or a 
sustained temperature of ≥38 degrees C for more than one hour. 
• 
Thrombocytopenia Grade 3 associated with any grade bleeding or Grade 4 
• 
Anaemia Grade ≥4 
Non-Hematological Toxicity 
• 
Nausea, vomiting or diarrhea Grade ≥3 despite optimal treatment 
• 
Signs of potential severe drug-induced liver injury as assessed according to Hy's law: 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 ULN and total 
bilirubin >2 ULN in the absence of cholestasis (alkaline phosphatase [ALP] <2 ULN) and 
no other reason can be identified. 
• 
Any other non-hematological toxicities: Grade ≥ 3 toxicities unless clear alternate etiology 
is documented by  the investigator and  except: 
o asymptomatic Grade 3 electrolyte changes that can be successfully supplemented 
(e.g., hypokalemia) and resolve/recover to baseline within 72 hours 
o Grade 3 fatigue that improves to ≤ Grade 2 in no more than 5 days 
o alopecia 
Other significant toxicity 
• 
Failure to complete the first cycle of treatment with at least 66% of the planned total dose 
due to toxicity possibly related to the study medication 
• 
Failure to start Cycle 2 for more than 1 week (day 36 or later) due to persistent Grade ≥ 2 
toxicities possibly related to the study medication, excluding fatigue 
• 
Any toxicity that is possibly related to the study medication and requires the withdrawal of 
the patient from the study during the DLT observation period 
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• 
Any on-study death not clearly due to underlying disease or extraneous causes 
For the Phase I part only, first cycle DLT analysis will be performed on the dose-limiting toxicity 
evaluable set. For each dose level, patients who experienced a DLT during the first cycle of 
treatment and type of DLT experienced, will be reported in a data listing. 
9.8.3. Deaths  
Frequency of deaths will be presented by study phase and dose level and relationship to the study 
treatment and according to the time since treatment discontinuation 
Date of death, primary reason for death and relation to study treatment will be provided in a data 
listing together with selected dosing information (dose level, date of first / last dose administration, 
number of cycles received of study treatment, time from last dose administered). Primary reason 
for death and time in days of occurrence of death since last dose of study treatment administered, 
will be tabulated. 
9.8.4. Clinical Laboratory Evaluations 
Quantitative laboratory variables (hematology, blood chemistry, coagulation) will be summarized 
using mean, standard deviation, minimum, maximum and median, by study phase and dose level 
at each visit. At each cycle, the same descriptive statistics of within-subject changes from baseline 
measurements will be also presented. 
The following laboratory data will be graded from Grade 1 up to Grade 4 according to the NCI 
CTCAE scale (version 5.0): hemoglobin (except Grade 4 for anemia), platelets, white blood cells 
(except Grade 4 for leukocytosis), neutrophils, lymphocytes, glucose (graded only for glucose 
decrease; i.e. hypoglycemia), sodium (graded only for sodium increase; i.e. hypernatremia), 
potassium (graded only for potassium increase; i.e. hyperkalemia), total calcium after correction 
with albumin, magnesium, creatinine, albumin (except Grade 4), aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-GT (GGT), total 
bilirubin and lactate dehydrogenase (LDH) (only Grade 1 possible). For lab tests reported in the 
NCI CTCAE scale for which the grading system is based mainly on clinical assessments, the grade 
will not be calculated. For example, this applies to eosinophils, glucose (hyperglycemia), 
phosphorus (both hyperphosphatemia and hyperphosphatemia), sodium (hyponatremia), 
potassium (hypokalemia) and INR. 
Laboratory abnormalities will be summarized in frequency distribution tables by study phase, dose 
level and treatment period (i.e. treatment Cycle 1, Cycle >1 and the whole treatment period).  
For each parameter graded according to NCI CTCAE scale, patients will be classified based on 
the maximal severity grade observed during the analyzed time-window. Changes of severity grade 
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vs. baseline will be evaluated by shift tables. Selected laboratory parameters will be further 
explored by analyzing the nadir/zenith values, the time to nadir/zenith and the time to recovery 
after nadir/zenith, as clinically appropriate. 
For the laboratory data not graded by the NCI CTCAE scale, a cross tabulation of on treatment 
worst finding versus baseline finding will be presented reporting the number of patients with values 
within or out of the normal range (i.e. hypo and/or hyper depending of the lab test considered), 
during the analyzed time-window. This analysis will be performed for the following lab tests: 
erythrocytes, monocytes, eosinophils, basophils, glucose (only for hyperglicemia), phosphorus, 
sodium (only for hyponatremia), potassium (only for hypokalemia), urea, blood urea nitrogen 
(BUN), total protein, unconjugated bilirubin. 
Laboratory results (hematology, blood chemistry, coagulation) will be listed for all treated 
patients by study phase, assigned schedule and dose level at each visit. All other parameters 
collected on the eCRF, i.e. urinalysis and pregnancy tests, will be listed in dedicated listings 
presenting all corresponding collected information on the eCRF. 
9.8.5. Other Safety Evaluations (e.g. Vital signs, ECG, ECOG PS, etc.) 
All vital sign parameters (i.e. systolic blood pressure, diastolic blood pressure and pulse), weight 
and BSA will be summarized using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum) of actual values and changes from baseline for each cycle with a 
minimum number of patients with at least one valid assessment. The maximum on-treatment 
change from baseline will be calculated and categorized by systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) measurements. Additionally, the worst assessment on treatment 
versus baseline, defined in terms of classes (i.e. normal BP: SBP < 140 mmHg and DBP < 90 
mmHg; abnormal BP: SBP≥140 mmHg and/or DBP ≥ 90 mmHg), will be summarized by shift table.  
The ECOG PS shift from baseline to highest score during the on-treatment period will be also 
summarized.  
Descriptive summaries of actual values and changes from baseline will be presented, for both 
Phase I and Phase II, for corrected Fridericia QT interval (QTc). The following additional ECG 
parameters collected in triplicate for patients enrolled in Phase II, will be also analyzed: synus 
rhythm, heart rate (HR), RR interval, PR interval, QRS interval, QT interval. The maximum on-
treatment change from baseline will be calculated and categorized by QTFc (for both Phase I 
and Phase II), HR, RR, PR and QRS (only for Phase II) measurements. Absolute frequency and 
percentage of treated patients with at least one clinically significant ECG abnormality during the 
treatment period will be summarized by category of ECG abnormalities. 
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Additionally, for all ECG parameters, the worst assessment on treatment versus baseline, defined 
in terms of classes, will be summarized by shift table. Frequency and percentage of treated patients 
with at least one clinically significant ECG abnormality during the treatment period will be 
summarized by category of ECG abnormalities.  
Vital signs data, weight, BSA, ECOG PS and ECG data (both quantitative and qualitative) will be 
also presented in data listings. 
9.9. Exploratory Analyses 
Exploratory analysis on the relationship between AFP levels and treatment efficacy variables 
in patients treated with NMS-01940153E will be performed if sufficient data are collected. 
Graphical display of AFP levels during the study will be used to support data interpretation. 
Exploratory analyses on biomarkers/molecular alteration in blood and tumor at baseline will be 
conducted based on the completeness of data collected. 
 
 
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10. REFERENCES 
 
1. https://www.ich.org/page/ich-guidelines 
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuckh S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe 
D, Verweij J. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). Eur. J. Cancer. 2009; 45 (228-247).  
3. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, 
Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier- 
Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, 
Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular 
carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-
blind, placebo-controlled, phase 3 trial. The Lancet. 2017 Jan;389 (10064):56-66. 
4. G.K. Abou‑Alfa, T. Meyer, A.-L. Cheng, A.B. El‑Khoueiry, L. Rimassa, B.-Y. Ryoo, I. Cicin, 
P. Merle, Y.H. Chen, J.-W. Park, J.-F. Blanc, L. Bolondi, H.-J. Klümpen, S.L. Chan, V. 
Zagonel, T. Pressiani, M.-H. Ryu, A.P. Venook, C. Hessel, A.E. Borgman‑ Hagey, G. 
Schwab, and R.K. Kelley Cabozantinib in patients with advanced and progressing 
hepatocellular carcinoma. N Engl J Med 2018; 379:54-63. 
5. Yau T , Hsu C, Kim TY, Choo SP, Kang YK, Hou M-M, Numata K, Yeo W, Chopra A, Ikeda 
M, Kuromatsu R, Moriguchi M, Chao Y, Zhao H, Anderson J, Dela Cruz C, Kudo M. 
Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort 
analysis. J. Hepatol. 2019; 71:543–552. 
6. Merle P, Edeline J, Bouattour M, Cheng AL, Lam Chan S, Yau T, Garrido M,. Knox JJ, 
Daniele B, Zhu AX, Vladimirovich Breder V, Lim HY, Ogasawara S, Siegel AB, Rahman A, 
Wei Z, Finn RS. Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) with advanced 
hepatocellular carcinoma (aHCC) previously treated with sorafenib: Updated data from the 
randomized, phase III KEYNOTE-240 study. J Clin Oncol 39, no. 3_suppl (January 20, 
2021) 268-268  
7. Li Q, Qin S, Gu S, Chen X, Lin L, Wang Z, Xu A, Chen X, Zhou C, Ren Z, Yang L, Xu L, 
Bai Y, Chen L, Li J, Pan H, Cao B, Fang W, Yan P, Jin C. Apatinib as second-line therapy 
in Chinese patients with advanced hepatocellular carcinoma: A randomized, placebo-
controlled, double-blind, phase III study. J Clin Oncol 38, no. 15_suppl (May 20, 2020) 
4507-4507. 
8. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for Hepatocellular 
Carcinoma Semin Liver Dis 2010 Feb;30(1):52-60 
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9. Bland J M, Altman D G. Survival probabilities (the Kaplan-Meier method) BMJ 1998;                  
317 :1572 doi:10.1136/bmj.317.7172.1572 
 
10. Schemper M., Smith TL; A note on Quantifying Follow-up in Studies of Failure Time; 
Control Clin Trials. 1996 Aug;17(4):343-6. 
 
11. Lagerlund O, Strese S, Fladvad M, Lindquist M. WHODrug: A Global, Validated and 
Updated Dictionary for Medicinal Information. Ther Innov Regul Sci. 2020 
Sep;54(5):1116-1122. doi: 10.1007/s43441-020-00130-6. Epub 2020 Feb 20. PMID: 
32078733; PMCID: PMC7458889. 
 
12. https://www.meddra.org/how-to-use/support-documentation/english 
 
13. Common Terminology Criteria for Adverse Events (CTCAE) 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
 
 
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11. APPENDICES 
 
The appendix “TLGs Mock-ups and Algorithms” is provided as a separate document. 
 
 
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12. APPROVAL AND SIGNATURES 
 
Author:  
                
  
 
 
Reviewers:  
 
 
 
 
 
 
 
  
 
 
Approver:  
 
 
 
 
Signature & 
Date : 
See electronic signature  
 
  
 
 
Signature & 
Date : 
See electronic signature  
 
 
 
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13. VERSION HISTORY 
Version N°. 
Effective Date 
Changes from the Previous Version 
1.0 
22-Oct-2021 
Initial Version (related to Protocol version 2.0 and eCRF Unique, 
Blank and Design Specifications version 2.0) 
2.0 
30-Jun-2023 
See Section 2.1  
 
 
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Signature Page for MPSA-153-001-02868 v1.0
Signature Page for MPSA-153-001-02868 v1.0
Reason for signing: Approved
Reason for signing: Approved
Reason for signing: Approved
Reason for signing: Approved
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