Unresectable hepatocellular carcinoma. MedDRA version: 20.0 Level: PT Classification code 10073071 Term: Hepatocellular carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: NMS-01940153E
Product Code: [NMS-01940153E]
Pharmaceutical Form: Powder for solution for infusion
Current Sponsor code: NMS-01940153E
Concentration unit: mg milligram(s)
Concentration ty
Sponsors
NERVIANO MEDICAL SCIENCES SRL
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 not exceeding 2 lines of prior systemic treatment. Subjects intolerant to previous treatment with TKIs are eligible. A minimum of 14 days of treatment with prior TKI would be required to qualify as line of therapy. 5. Child-Pugh score or =18 years old on day of consent. 8. No history of liver transplantation or not listed for high urgent transplantation. 9. Blood test adequate; adequate liver function, defined by the values of serum transaminases (ie, AST / ALT) 60 mL /min. 10. In case of active hepatitis B (HBV) infection the patient should receive antiviral therapy per local standard of care. 11. Female subjects must be surgically sterile or be postmenopausal or, if subjects of childbearing potential, must not be pregnant at screening and must agree to the use of effective contraception during the period of therapy and in the following 90 days after discontinuation of study treatment. Male subjects must be surgically sterile or must agree to use effective contraception 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 =65 years) yes F.1.3.1 Number of subjects for this age range 36
Exclusion criteria
Exclusion criteria: 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 exception of subjects with history of prior variceal bleeding treated with adequate endoscopic therapy without any evidence of recurrent bleeding for at least 6 months prior to study entry and stable on optimal medical management at study entry. 3. Subjects with QTcF interval > o = 480 milliseconds or with risk factors for torsade de pointes 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> o =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 . 6. Direct-Acting Antivirals (DAA) at the time of treatment start; previous HCV treatment with DAAs is allowed. 7. Known history of or current 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. 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 (eg, I-131 or Y-90) within 6 weeks before treatment start. 14. Untreated uncontrolled bacterial, viral, or fungal infections . 15. Subjects under treatment with therapeutic dose of anticoagulants or antiplatelet agents 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 FMO1and FMO3. 24. Subjects who are receiving sensitive CYP3A4 substrates, CYP3A4 and BCRP substrates with narrow therapeutic index (NTI).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main 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 evaluate the anti-tumor efficacy of NMS-01940153E administered as single agent to adult patients with unresectable hepatocellular carcinoma previously treated with systemic therapy on the basis of the progression free survival rate at 4 months from treatment initiation (Phase II).;Secondary Objective: •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;Primary end point(s): •Drug related Dose Limiting Toxicities (DLTs) (Phase I). •Progression Free Survival rate at 4 months (PFS-4 rate). The PFS-4 rate will be calculated as the proportion of evaluable patients known to be alive and progression free measured by RECIST 1.1, at > or =4 months since study treatment start out of the total number of evaluable patients (Phase II).;Timepoint(s) of evaluation of this end point: Phase I: During the first cycle. Phase II: Four months after the tretment start. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Objective Tumor Response (Partial and Complete Response) as measured by RECIST 1.1 (Phase I).; 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 abnormalities, and relationship of the AEs to study treatment in the first and subsequent cycles of therapy.; Overall response rate (ORR) as measured by RECIST 1.1 (Phase II).; Duration of response (DoR) as measured by RECIST 1.1.; Pharmacokinetic parameters of NMS-01940153E and its main metabolite NMS-03593478 in plasma and urine (urine only in Phase I); Progression Free Survival as measured by RECIST 1.1.; Overall survival (OS).;Timepoint(s) of evaluation of this end point: Baseline ìmaging tumor assessments performed within 4 weeks prior to the start of treatment;on treatment, tumor assessments performed every even cycle (i.e., end of Cycle 2, 4, 6, etc. or whenever a clinical deterioration is observed) and at the End of Treatment vìsìt (if not done in the prevìous 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.; All the study duration.; Baseline ìmaging tumor assessments performed within 4 weeks prior to the start of treatment; on treatment, tumor assessments performed every even cycle (i.e., end of Cycle 2, 4, 6, etc. or whenever a clinical deterioration is observed) and at the End of Treatment vìsìt (if | — |
Countries
Italy, Spain
Contacts
Public ContactGlobal Clinical Development
Nerviano Medical Sciences S.r.l.
Outcome results
None listed