Study Investigating the Association of NP137 With Atezolizumab-Bevacizumab Combination in First Line in Unresectable HCC

Hepatocellular Carcinoma Clinical Trial

— Liver-NET1  

Official title:

Study Investigating the Association of NP137 With Atezolizumab-Bevacizumab Combination in First Line in Unresectable Hepatocellular Carcinoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05546879
• Other study ID #: 38RC22.210
• Status: Recruiting
• Phase: Phase 1
• Start date: March 15, 2023
• Est. completion date: November 15, 2025

Study information

• Verified date: December 2023
• Source: University Hospital, Grenoble
• Contact: Anna BOROWIK
• Phone: 0476769314
• Email: aborowik[@]chu-grenoble.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study will assess the safety of the association of NP137 with the standard of care Atezolizumab-Bevacizumab in first line setting in patients with unresectable hepatocellular carcinoma.The study drug which is tested is the NP137 in association with Atezolizumab-Bevacizumab to allow a better tumor response as well as better survival outcomes with an acceptable safety.

Description:

The study is a multicentric, prospective, single arm phase 1b trial. This study will enroll 43 to 52 patients and consists of 2 parts: Safety Lead-in Phase and Expansion Phase. Initially, 3 to 12 patients will be enrolled into a Safety Lead-in Phase based on a 3 + 3 design, with the possibility of dose de-escalation, to confirm the recommended dose of NP137 .The Expansion Phase will start after completion of Safety Lead-in Phase at the confirmed dose and will include 40 patients. Patients will be assigned to the experimental single arm (NP137+ Atezolizumab-Bevacizumab).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 52
• Est. completion date: November 15, 2025
• Est. primary completion date: November 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Males or females = 18 years of age

2. Histologically confirmed (liver biopsy within 24 previous weeks) and documented unresectable hepatocellular carcinoma

3. Patients with a BCLC C status, as per the Barcelona Clinic Liver Cancer (BCLC) staging system

4. No prior systemic therapy for advanced HCC

5. Patients uneligible to transarterial chemoembolization

6. Liver tumor burden < 50% of the liver (per Investigator judgment)

7. Child-Pugh A (= 6) without any history of cirrhotic decompensation within the past 6 months

8. Antiviral therapy required in hepatitis B virus patients (Hepatitis B antigen positive)

9. Willing to have liver biopsy between C4 and C5

10. Presence of a measurable tumor per RECIST v1.1 criteria

11. Eastern Cooperative Oncology Group (ECOG) performance status = 1

12. Life expectancy = 12 weeks

13. Absence of previous liver decompensation

14. In case of cirrhosis, last esophageal varices detection by esogastroduodenal endoscopy have to be performed within last the 6 months before inclusion

15. Adequate hematologic function prior to the first dose of NP137, defined as:

Absolute neutrophils count = 1500 cells/µL 15.2. Hemoglobin = 9 g/dL with no transfusion within 4 weeks prior to first planned dose of NP137 15.3. Platelet count > 50,000/µL with no transfusion within 2 weeks prior to first planned dose of NP137

16. Adequate renal function prior to first dose, defined as:

16.1. Serum creatinine < 1.5 × Upper limit of normal (ULN ) 16.2. Creatinine clearance = 30 mL/min/m2 (by Cockroft-Gault equation of 24-hour urine) if creatinine = 1.5 × ULN

17. Adequate hepatic function prior first dose, defined as AST/ALT = 5 × ULN

18. Women patients of childbearing potential must have a negative serum pregnancy test at screening and baseline, and be willing to use a highly effective contraception. The patient should be advised to continue the contraception for at least 6 months following the completion of dosing. Women with cessation for > 24 months of previously occurring menses, or women of any age who have had a hysterectomy, or have had both ovaries removed will be considered to be of non-childbearing potential.

19. Male patients of reproductive potential must be willing to use one acceptable method of contraception, as judged by Investigator and Sponsor and/or to refrain from donating sperm from the time of screening through at least 6 months following the completion of dose administration.

20. Amenable to computed tomography (CT) with 3 or 4 phase liver or magnetic resonance imaging (MRI) of abdomen and pelvis, and CT of chest, or MRI of whole body, for initial tumor size measurements and subsequent follow-up.

21. Absence of other clinically relevant abnormalities for any screening laboratory test results as judged by the Investigator and Sponsor.

22. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

23. Able to understand and provide written informed consent

24. Patients covered by Health Insurance System

Exclusion Criteria:

1. Any known history of encephalopathy

2. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding

3. Known esophageal varices with recent history of bleeding (within previous 6 months)

4. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures

5. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

6. Chronic treatment with immunosuppressive agents (like steroids) = 6 weeks prior to first planned dose of treatment.

7. Major surgical procedures, open biopsy or significant traumatic injury = 4 weeks prior to first dose of treatment or anticipation of major surgical procedure during the course of the trial, minor surgical procedures = 1 week of first planned dose (the surgical wound must be fully healed)

8. Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure

9. Any clinically significant cardiovascular condition as judged by the Investigator (such as New York Heart Association Class II or greater cardiac failure, myocardial infarction, or cerebrovascular accident within 3 months prior to Day 1 of Cycle 1, uncontrolled arterial hypertension, unstable arrhythmia, or unstable angina)

10. Severe or uncontrolled renal condition

11. Untreated chronic hepatitis B

12. Co-infection of HBV and HCV

13. Use of any prohibited concomitant medications within 14 days of the Baseline/Day 1 visit

14. Contraindication to additionnal liver biopsy planned between C4 and C5

15. Contraindication to iodinated contrast agent infusion

16. Known current alcohol (> 20g/ Day in women and > 30g/ Day in men) or substance abuse

17. History of leptomeningeal disease

18. Active or history of autoimmune disease or immune deficiency

19. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan

20. Known active tuberculosis

21. History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death

22. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 6 months after the last dose of treatment

23. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases

24. Uncontrolled tumor-related pain

25. Uncontrolled or symptomatic hypercalcemia

26. Treatment with systemic immunostimulatory agents

27. Inadequately controlled arterial hypertension

28. Prior history of hypertensive crisis or hypertensive encephalopathy

29. Evidence of bleeding diathesis or significant coagulopathy

30. History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration

31. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

32. Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses

33. Known clinically significant or life threatening organ or systemic disease such that in the opinion of the Investigator, the significance of the disease will compromise the patient's participation in the trial

34. Known intolerance or hypersensitivity to the active ingredient or to one of the components of the study drug

35. Persistent toxicities related to prior treatment of grade greater than 1

36. Subjects with active infection

37. History of bone marrow allograft or solid organ transplant

38. Subjects requiring corticosteroid therapy at a dose equivalent to more than 10 mg of prednisone equivalent dose per day (corticosteroid administration is permitted by a route resulting in minimal systemic exposure [cutaneous, rectal, articular, ocular or inhalation] is authorized).

39. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies

40. History of gastrointestinal perforations and fistulae

41. Uncontrolled or symptomatic proteinuria

42. History of aneurysm

43. Patients who experienced immune-mediated pericardial disorders during previous treatment by immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1 therapeutic antibodies

44. Subject in exclusion period for another study,

45. Subject who cannot be contacted in case of emergency

46. Persons referred to in Articles L1121-5 to L1121-8 of the French code of public health (this corresponds to all persons protected: pregnant or parturient women, breastfeeding mothers, persons deprived of liberty by judicial or administrative decision, persons subject to a legal protection measure).

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• NP137
NP137 at 9 or 14 mg/kg IV will be administered every 21 days.
• Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-days cycle
• Bevacizumab
Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle

Locations

Country	Name	City	State
France	CHU de GRENOBLE ALPES	Grenoble	Alpes

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Grenoble	NETRIS Pharma

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall survival (OS)	Median Overall survival (OS) and 12 months-OS rates. OS is defined as the time between inclusion and death (all causes). Patients alive will be censored at the date of last news.	at 12 and 36 months
Other	Progression-Free Survival (PFS)	Median Progression-Free Survival (PFS) and 12 months-PFS rates according to RECIST 1.1.	at 12 and 36 months
Other	Duration of response	Median Duration of response is defined as the time between first dose of treatment and progression according to RECIST 1.1. Patients alive without progression will be censored at the date of last news.	at 36 months
Other	Alpha-fetoprotein (AFP) response	AFP response will be defined as a percentage of patients with a = 50% reduction from baseline AFP level, at 3, 6, 12 months	At 3,6, and12 months
Other	Quality of life (QoL)	QoL will be studied by using the EORTC QLQ-C30 and QLQ-HCC18 questionnaire (European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire for Cancer) at baseline, 3, 6, 12 months. A 5-point decrease of QLQ-C30 score will be considered as the minimal clinically significant deterioration of QoL.	At 3,6, and12 months
Other	time to deterioration (TTD)	TTD will be defined as the time from inclusion in the study to deterioration of EORTC QLQ-C30 score with a decrease =5 points at any time point after the baseline score.	at 36 months
Other	PK-PD evaluation	based on available PopPK modelisation and PK samples collected at the time of the response evaluation in this study	At 36 months
Primary	Percentage Proportion of patients experiencing adverse events	Percentage Proportion of patients experiencing adverse events (AEs) of any grade and grade 3/4 AEs as defined by the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE v 5.0) throughout the study period.	At 36 months
Secondary	Best overall objective response rate (ORR)	Best overall objective response rate (ORR) and ORR at 3 months, 6, 9, 12 months according to mRECIST and RECIST 1.1.	At 3,6,9,12 months