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Nivolumab in Combination With TACE for Patients With Intermediate Stage HCC (TACE-3)

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ClinicalTrials.gov Identifier: NCT04268888
Recruitment Status : Recruiting
First Posted : February 13, 2020
Last Update Posted : February 13, 2020
Sponsor:
Information provided by (Responsible Party):
The Clatterbridge Cancer Centre NHS Foundation Trust

Brief Summary:
This study evaluates the addition of nivolumab to TACE (DC Bead eluting doxorubicin) in the treatment of patients with intermediate stage hepatocellular carcinoma. All patients will receive TACE and half will receive nivolumab.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: Nivolumab and TACE Procedure: TACE Phase 2 Phase 3

Detailed Description:

A significant proportion of HCC patients present with, or progress to, intermediate stage disease and these patients are typically treated with transarterial chemo-embolisation (TACE).

However, since TACE is generally a palliative therapy, it provides a potential backbone for the addition of effective systemic therapies with the aim of improving survival outcomes. Since TACE may liberate an abundance of tumour antigens and 'danger' signals, it may lend itself to combination with immunotherapeutic strategies.

Doxorubicin is an anthracycline antibiotic with antineoplastic activity. Doxorubicin, isolated from the bacterium Streptomyces peucetius var. caesius, is the hydroxylated congener of daunorubicin. Doxorubicin intercalates between base pairs in the DNA helix, thereby preventing DNA replication and ultimately inhibiting protein synthesis. Additionally, doxorubicin inhibits topoisomerase II which results in an increased and stabilized cleavable enzyme-DNA linked complex during DNA replication and subsequently prevents the ligation of the nucleotide strand after double-strand breakage. Doxorubicin also forms oxygen free radicals resulting in cytotoxicity secondary to lipid peroxidation of cell membrane lipids; the formation of oxygen free radicals also contributes to the toxicity of the anthracycline antibiotics, namely the cardiac and cutaneous vascular effects.

Nivolumab is a human monoclonal antibody. Nivolumab targets the programmed death-1 PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 522 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients shall be randomised on a 1:1 basis throughout the study and allocated using pre-generated lists produced by the study statistician. List shall be produced using permuted blocks algorithm with random block sizes of 2 and 4. Stratification factors used in the study are randomising centre, baseline HAP score (A vs. B vs. C) and vascular invasion (No vs. Yes).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two-arm Multi-stage (TAMS) Seamless Phase II/III Randomised Trial of Nivolumab in Combination With TACE for Patients With Intermediate Stage HCC
Actual Study Start Date : May 8, 2019
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Active Comparator: TACE
Transarterial Chemoembolisation using DC Beads™ (TACE) loaded with doxorubicin ALONE.
Procedure: TACE
TACE (DC Bead loaded with doxorubicin hydrochloride)

Experimental: TACE and Nivolumab
As above for TACE. Nivolumab adminstered as a flat dose of 480mg IV.
Drug: Nivolumab and TACE
Immunotherapy and TACE

Procedure: TACE
TACE (DC Bead loaded with doxorubicin hydrochloride)




Primary Outcome Measures :
  1. Overall Survival - phase III primary outcome [ Time Frame: The time until death. Patients discontinuing the study, lost to follow-up or still alive at the end of the study will be censored at the last know date alive, this can be assessed up until 2 years after the last patient. ]
    Measured in days

  2. Time to TACE Progression (TTTP) - phase II primary outcome [ Time Frame: The time to confirmatory scan 4 weeks after progression this can be assessed up until 2 years after the last patient is randomised ]
    Measured in days


Secondary Outcome Measures :
  1. Time to Progression [ Time Frame: Time to date of progression confirmed by RECIST1.1 assessed up until 2 years after the last patient is randomised ]
    Measured in days

  2. Radiological response rate [ Time Frame: Through study completion ]
    RECIST 1.1

  3. Safety and Toxicity: the number and percentage of patients reporting a Serious Adverse Event (SAE) and Grade 3 or higher Adverse Event (AE) [ Time Frame: Through study completion ]
    the number and percentage of patients reporting a Serious Adverse Event (SAE) and Grade 3 or higher Adverse Event (AE), measured and categorised based on CTCAE (version 4).

  4. Progression Free Survival [ Time Frame: Time to progression or death. Assessed up until 2 years. ]
    Measured in days

  5. QOL: EORTC QLQ-C30 [ Time Frame: baseline, pre - TACE (first treatment) and 12 weekly thereafter until end of treatment. Assessed up until 2 years after the last patient is randomised ]
    QoL will be scored according to the EORTC QLQ-C30 manual and guidelines.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histological diagnosis of HCC and at least one uni-dimensional lesion measurable according to RECIST 1.1 criteria by CT-scan or MRI.
  2. Not a candidate for surgical resection or liver transplantation
  3. Aged ≥16 years and estimated life expectancy >3 months
  4. ECOG performance status 0-1
  5. Adequate haematological function:

    • Hb ≥9g/L
    • Absolute neutrophil count ≥1.0x109/L
    • Platelet count ≥60x109/L
  6. Bilirubin ≤50 μmol/L, AST,ALT and ALP ≤5 x ULN
  7. Adequate renal function; Creatinine ≤ 1.5ULN (Using Cockcroft-Gault Formula)
  8. INR ≤1.6
  9. Child-Pugh A (score ≤6) (Appendix D)
  10. HAP score A, B or C (Appendix E)
  11. No contra-indications to T-cell checkpoint inhibitor therapy (use of immunosuppressive drugs including steroids at dose equivalent to prednisolone >10mg/day unless used as replacement therapy; organ transplantation; subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, lichen planus or other conditions not expected to recur in the absence of an external trigger are permitted to enrol).
  12. Women of child-bearing potential should have a negative pregnancy test prior to study entry. Both men and women must be using an adequate contraception method, which must be continued for 5 months after completion of treatment for women and 7 months for men
  13. Written informed consent

Exclusion Criteria:

  1. Extrahepatic metastasis
  2. Prior embolisation, systemic or radiation therapy for HCC
  3. Any contraindications for hepatic embolisation procedures including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis
  4. Investigational therapy or major surgery within 4 weeks of trial entry
  5. History of variceal bleeding within the past 4 weeks
  6. Child-Pugh cirrhosis B or C (score ≥7)
  7. HAP score D
  8. Hepatic encephalopathy
  9. Ascites refractory to diuretic therapy
  10. Documented occlusion of the hepatic artery or main portal vein5
  11. Hypersensitivity to intravenous contrast agents
  12. Active clinically serious infection > Grade 2 NCI-CTC
  13. Pregnant or lactating women
  14. Known history of HIV infection
  15. HBV chronic infection with HBV DNA > 500IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated.

17. History of second malignancy except those treated with curative intent more than three years previously without relapse and non-melanotic skin cancer or cervical carcinoma in situ 18. Evidence of severe or uncontrolled systemic disease, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial 19. Psychiatric or other disorder likely to impact on informed consent 20. Patient is unable and/or unwilling to comply with treatment and study instructions 20. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity

21. Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or antifungal therapy within 7 days prior to administration of study medication

22. Positive test for latent TB or evidence of active TB

23. Hypersensitivity to any of the active substances or excipients

24. Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment

25. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration

26. Any uncontrolled inflammatory GI disease including Crohn's Disease and ulcerative colitis

27. Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04268888


Contacts
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Contact: Maria Maguire, PhD 0151 556 maria.maguire2@nhs.net
Contact: David Price 0151 556 david.price9@nhs.net

Locations
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United Kingdom
University of Liverpool Recruiting
Liverpool, United Kingdom, L69 7ZB
Contact: Louise Handley    0151 794 8935    louise.handley@liverpool.ac.uk   
Principal Investigator: Daniel Palmer, PhD, MD         
Sponsors and Collaborators
The Clatterbridge Cancer Centre NHS Foundation Trust
Investigators
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Study Director: Daniel Palmer, PhD, MD Clatterbridge Cancer Centre

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Responsible Party: The Clatterbridge Cancer Centre NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT04268888    
Other Study ID Numbers: CA209-9Y9
First Posted: February 13, 2020    Key Record Dates
Last Update Posted: February 13, 2020
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by The Clatterbridge Cancer Centre NHS Foundation Trust:
Intermediate Stage
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Nivolumab
Chlorotrianisene
Antineoplastic Agents, Immunological
Antineoplastic Agents
Estrogens, Non-Steroidal
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal