Study on Safety and Efficacy of NMS-01940153E in Adult Patients With Unresectable Hepatocellular Carcinoma (HCC) Previously Treated With Systemic Therapy

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.


Eligibility Criteria:
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 tyrosine kinase inhibitors (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).
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. Meets required laboratory data
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 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 National Cancer Institute (NCI) common terminology criteria (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 independent ethics committee (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.

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.
3. Subjects with QT interval using Fridericia standard (QTcF) ≥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 hepatitis C virus (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 international normalized ratio (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 flavin-containing monooxygenase FMO1 and FMO3.
24. Subjects who are receiving sensitive CYP3A4 substrates, CYP3A4 and breast cancer resistance protein (BCRP) substrates with narrow therapeutic index (NTI).