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

Phase 1

Terminated

Conditions: Unresectable Hepatocellular Carcinoma (HCC)

Interventions: Drug: NMS-01940153E

Registration Number: NCT05630937

Lead Sponsor: Nerviano Medical Sciences

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: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 31

Inclusion Criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:

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.
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).
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.
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;
Child-Pugh score ≤ 6 (class A).
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Age ≥18 years old on day of consent.
No history of liver transplantation or not listed for high urgent transplantation.
Meets required laboratory data
In case of active hepatitis B (HBV) or chronic HIV infection the patient should receive antiviral therapy per local standard of care.
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.
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.
Able and willing to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol.
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:

Known fibrolamellar HCC or mixed hepato-cholangiocarcinoma.
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.
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.
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.
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).
Direct-Acting Antivirals (DAA) at the time of treatment start; previous hepatitis C virus (HCV) treatment with DAAs is allowed.
Clinical evidence of hepatic encephalopathy.
Known brain metastases or evidence of leptomeningeal disease.
Known history of allergic reactions to polysorbate 80.
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).
Major surgery, other than diagnostic surgery, within 4 weeks before treatment start.
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.
Radiation therapy within 4 weeks or radionuclide treatment (e.g., I-131 or Y-90) within 6 weeks before treatment start.
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.
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.
Uncontrolled diabetes mellitus.
Pregnant or breast-feeding women.
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.
Current enrollment or participation in another interventional clinical trial.
Clinically significant respiratory or metabolic diseases uncontrolled by medication.
Subjects with active alcohol and/or substances abuse.
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.
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.
Subjects who are receiving sensitive CYP3A4 substrates, CYP3A4 and breast cancer resistance protein (BCRP) substrates with narrow therapeutic index (NTI).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
NMS-01940153E	NMS-01940153E	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.

Primary Outcome Measures

Name	Time	Method
Phase I Drug Related Dose Limiting Toxicities (DLTs)	Phase I: From screening to end of first 28-day cycle (17 months)	All 12 Phase I treated patients were evaluable for DLT (Dose-Limiting Toxicity Evaluable Set) and included 6 patients treated at each of the two dose levels explored (i.e., 100 mg/m2/week and 135 mg/m2/week) who received at least 66% of the study drug in the first 28-day cycle of treatment and underwent a DLT assessment within the DLT window. Participants who experienced DLTs are presented.
Phase II Objective Response Rate	Phase II: From Phase II start to Study Completion (23 months)	The objective response rate (ORR) was calculated as the proportion of evaluable patients who achieved, as best overall response (BOR), confirmed complete response (CR) or partial response (PR) measured by investigator-assessed RECIST 1.1 (Phase II).

Secondary Outcome Measures

Name	Time	Method
Phase I: Duration of Response (DoR) as Measured by Investigator-assessed RECIST 1.1	Phase I: From the Study Start Date to Phase I Completion (32 months)	Duration of response (DoR) as measured by investigator-assessed Response evaluation criteria in solid tumours (RECIST) 1.1. Duration of Response (months): was time in months from response start date to either date of disease progression/death due to progression of disease. It was calculated only for participants with complete response or partial response as best overall response.
Treatment-emergent Adverse Events by Maximum CTC Grade	Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months)	The maximum Common Terminology Criteria (CTC) grade (graded using National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] Version 5.0) experienced by each participant is presented. If an AE was reported for a participant more than once during treatment, the worst CTC Grade is presented here. Phase 2 started before Phase 1 completed. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.
Phase I Objective Tumor Response (Partial and Complete Response)	Phase I: From the Study Start Date to Phase I Completion (32 months)	Phase I any dose level, objective response and best overall tumor response are presented, as measured by investigator assessed RECIST 1.1 (Phase I). The objective response rate was calculated as the proportion of evaluable patients who achieved best overall response (BOR), confirmed complete response (CR) or partial response (PR).
Phase II Objective Response Rate as Measured by Investigator-assessed mRECIST	Phase II: From Phase II start to Study Completion (23 months)	Objective response rate as measured by investigator-assessed mRECIST in Phase II.
Treatment-emergent Adverse Events Related to NMS-01940153E	Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months)	The number of treatment-emergent adverse events related to NMS-01940153E by maximum CTC grade experienced (graded using NCI CTCAE Version 5.0). Whether the the AE was related or not was assessed by the investigator. If an AE was reported for a participant more than once during treatment, the worst CTC Grade is presented. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening. Phase 2 started before Phase 1 completed.
Hematology: Overall Treatment-emergent Abnormalities by Dose Level and Maximum CTC Grade	From screening to 28 days follow-up, an average 6 months	Number of treatment emergent abnormalities (at any grade) at all dose levels are presented. CTC = Common Terminology Criteria WBC = white blood cells
Neutrophils Count Decrease: Time to First Occurrence of >=Grade 3 and Time to Recovery to Grade 1	From screening to 28 days follow-up, an average 6 months	The mean days to first occurrence of neutrophil count decrease are presented for all dose levels. Grade 0: ≥2,000/mm3 Grade 1: ≥1,500-\< 2,000/mm3 Grade 2: ≥1,000- \< 1,500/mm3 Grade 3: ≥500- \< 1,000/mm3 Grade 4: \<500/mm3 * G3 = Time (days) to Treatment Start to First Occurrence of Neutrophil Count Decrease \>=Grade 3 * G3 to Recovery to G1 = Time (days) to First Occurrence of Neutrophil Count Decrease \>= Grade 3 to Recovery to Grade 1
Blood Chemistry: Treatment-emergent Abnormalities by Dose Level	From screening to 28 days follow-up, an average 6 months	Treatment-emergent abnormalities in blood chemistry at any grade are presented by dose level. ALP = Alkaline phosphatase ALT = Alanine aminotransferase AST = Aspartate aminotransferase GGT = Gamma-glutamyl transferase LDH = Lactate dehydrogenase
Blood Chemistry and Coagulation: Treatment-emergent Abnormalities	From screening to 28 days follow-up, an average 6 months	Treatment Emergent abnormalities by dose Level are presented for blood chemistry and coagulation parameters. INR = international normalized ratio LNL = lower normal limit NL = normal limit ULN = upper limit of normal
Electrocardiogram Abnormalities	From screening to 28 days follow-up, an average 6 months	The number of participants who experienced electrocardiogram abnormalities are presented.
Tmax and Tlast of NMS-01940153E	Day 1 to Day 15	Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Tmax = Time to maximum observed plasma concentration Tlast = Time of last detectable concentration
Cmax and Clast of NMS-01940153E	Day 1 to Day 15	Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Cmax = Maximum observed plasma concentration Clast = Last detectable concentration
AUClast, AUCweekly, and AUCinf of NMS-01940153E	From Days 1 to 21 (168 hours after the Day 15 infusion)	Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Infusions occurred on Days 1, 8, and 15. AUClast = Area under the interpolated observed plasma time-concentration curve from infusion start to the last observed plasma concentration AUCweekly = Area under the interpolated observed plasma time-concentration curve from infusion start to 168 hours AUCinf = Area under the interpolated observed plasma time-concentration curve from infusion start extrapolated to infinity based on the last observed plasma concentration
t½,z of NMS-01940153E	Day 1 to Day 15	Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. t½,z = Half-life of the terminal phase of observed plasma concentration
CL and CLss of NMS-01940153E	Day 1 to Day 15	Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. CL = Clearance based on last observed concentration and extrapolation to infinity CLss = Clearance calculated for a dosing period of 168 h either after a single dose or in steady-state
Vss and Vss,SS of NMS-01940153E	Day 1 to Day 15	Plasma pharmacokinetic (PK) PK profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Vss = Volume of distribution at steady state based last observed concentration extrapolated to infinity and Clearance calculated for a dosing period of 168 h either after a single dose or in steady-state Vss,SS = Volume of distribution at steady state based last observed concentration extrapolated to infinity and clearance based on last observed concentration and extrapolation to infinity
RA AUCweekly and RA Cmax of NMS-01940153E	Day 21 (168 hours after the Day 15 infusion)	Plasma pharmacokinetic (PK) PK profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Infusions occurred on Days 1, 8, and 15. RA AUCweekly = Accumulation ratio Day 1 to 15 calculated using area under the interpolated observed plasma time-concentration curve from infusion start to 168 hours RA Cmax = Accumulation ratio Day 1 to 15 calculated using maximum observed plasma concentration
FE of NMS-01940153E	Day 1 to Day 15	Urine pharmacokinetic profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. FE = Molar fraction of excreted compound relative to the administered molar dose calculated using urine concentration and volume data
Phase II: Duration of Response (DoR) as Measured by Investigator-assessed RECIST 1.1. and Investigator-assessed mRECIST	Phase II: From Phase II start to Study Completion (23 months)	Duration of response (DoR) as measured by investigator-assessed Response evaluation criteria in solid tumours (RECIST) 1.1 and investigator-assessed modified RECIST (mRECIST). Duration of Response (months): was time in months from response start date to either date of disease progression/death due to progression of disease. It was calculated only for participants with complete response or partial response as best overall response.
Progression Free Survival, as Measured by Investigator-assessed RECIST 1.1, in Phases I and II	Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months)	Progression Free Survival as measured by investigator assessed RECIST 1.1, for all treated participants in Phase I and Phase II. Phase 2 started before Phase 1 completed.
Overall Survival in Phases I and II	Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months)	Overall Survival for all treated participants in Phases I and II. The estimates are based on the Kaplan-Meier (KM) method. Phase 2 started before Phase 1 completed.

Trial Locations

Locations (9): Fondazione IRCCS Istituto Nazionale dei Tumori
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Milano, Italy
Istituto Oncologico Veneto - IRCCS
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Padova, Italy
University of California Irvine Health
🇺🇸
Orange, California, United States
Azienda Ospedaliero Universitaria Pisana - Ospedale Santa Chiara
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Pisa, Italy
Azienda Ospedaliera Ordine Mauriziano di Torino
🇮🇹
Torino, Italy
Siteman Cancer Center - Washington University Medical Campus
🇺🇸
Saint Louis, Missouri, United States
Azienda Sanitaria Locale Napoli 1 Centro - Ospedale del Mare
🇮🇹
Naples, Italy
Istituto Clinico Humanitas
🇮🇹
Rozzano, Italy
Hospital Clínic de Barcelona
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Barcelona, Spain