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Durvalumab (MEDI4736) and Tremelimumab for Hepatocellular Carcinoma in Patients Listed for a Liver Transplant

Primary Purpose

Hepatocellular Carcinoma, Cirrhosis, Portal Hypertension

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Durvalumab
Tremelimumab
Liver Transplant
Sponsored by
Davendra Sohal
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring Transplant

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Hepatocellular carcinoma, diagnosed either by biopsy or by combination of cirrhosis and imaging criteria (contrast-enhanced CT or MRI).
  2. Tumor within UCSF criteria for transplant: either one lesion ≤6.5 cm; or up to 3 lesions, none >4.5 cm, with a total diameter ≤8 cm, with no vascular invasion and no evidence of extrahepatic disease.
  3. Patient evaluated by institutional Liver Transplant team and listed for transplant.
  4. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization.
  5. No prior therapy for HCC at any time.
  6. Age ≥18 years at the time of study entry.
  7. ECOG score of 0 or 1
  8. Child-Pugh Score of 5, 6, or 7
  9. Body weight >30 kg
  10. Patients must have adequate organ and marrow function as defined in protocol
  11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  12. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

  1. Extrahepatic disease.
  2. Variceal bleeding during 3 months prior to registration.
  3. Any autoimmune disease deemed a risk in the setting of immunotherapy per treating physician's judgment.
  4. Any other illness or patient condition deemed a medical or logistical barrier for protocol therapy per treating physician's judgment.
  5. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
  6. Participation in another clinical study with an investigational product during the last 12 months Patients who have received other investigational agents previously who are no longer receiving these investigational agents may be eligible at the discretion of the PI.
  7. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  8. History of allogenic organ transplantation.
  9. History of another primary malignancy except for:

    1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    3. Adequately treated carcinoma in situ without evidence of disease
  10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. Patients with celiac disease controlled by diet alone
  11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
  12. History of leptomeningeal carcinomatosis
  13. History of active primary immunodeficiency
  14. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  15. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  16. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
  17. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy.
  18. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  19. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
  20. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

Sites / Locations

  • Washington University School of MedicineRecruiting
  • University of CincinnatiRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Durvalumab + Tremelimumab + Liver Transplant

Arm Description

Patients will be treated with the immunotherapy combination for up to 4 months. After a minimum 28 day washout, they will undergo locoregional therapy per institutional standards. Eventually, after a minimum 72-day washout from the end of immunotherapy, they will undergo liver transplant.

Outcomes

Primary Outcome Measures

Cellular rejection rates
To assess the safety of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to cellular rejection rates

Secondary Outcome Measures

Adverse events during treatment, and graft loss and mortality rates
To assess the safety of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to adverse events during treatment, and graft loss and mortality rates up to 30 days after transplant;
Radiologic responses via RECIST 1.1 and/or mRECIST
To assess the efficacy of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to radiologic responses
Pathologic responses via explanted liver assessment
To assess the efficacy of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to Pathologic responses
Recurrence-free survival and overall survival outcomes based on survival follow up reporting
To assess the efficacy of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to Survival outcomes

Full Information

First Posted
August 17, 2021
Last Updated
April 4, 2023
Sponsor
Davendra Sohal
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1. Study Identification

Unique Protocol Identification Number
NCT05027425
Brief Title
Durvalumab (MEDI4736) and Tremelimumab for Hepatocellular Carcinoma in Patients Listed for a Liver Transplant
Official Title
Durvalumab (MEDI4736) and Tremelimumab for Hepatocellular Carcinoma in Patients Listed for a Liver Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 7, 2021 (Actual)
Primary Completion Date
December 7, 2025 (Anticipated)
Study Completion Date
December 7, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Davendra Sohal

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Immunotherapy can safely downstage patients and achieve durable systemic disease control to improve clinical outcomes in HCC patients undergoing liver transplant.
Detailed Description
ESR-20-21010 is a single-arm, open-label, Phase II, multicenter clinical trial designed to evaluate the safety and efficacy of durvalumab and tremelimumab for the treatment of hepatocellular carcinoma (HCC) patients who have cirrhosis or portal hypertension and are listed for a liver transplant. The key eligibility requirements include HCC within UCSF criteria, Child-Pugh score of up to 7, and ECOG PS of 0 or 1. Patients will be treated with the immunotherapy combination for up to 4 months. After a minimum 28 day washout, they will undergo locoregional therapy per institutional standards. Eventually, after a minimum 72-day washout from the end of immunotherapy, they will undergo liver transplant. The primary endpoint is proportion of patients experiencing post-transplant rejection (within 30 days of transplant). A total of 30 patients are to be enrolled, to allow at least 20 transplants for adequate primary endpoint analysis. An interim analysis after 10 patients will be performed to ensure safety. If there are untoward safety signals, study modification/discontinuation will be discussed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma, Cirrhosis, Portal Hypertension
Keywords
Transplant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Single-arm, open-label, Phase II, multicenter clinical trial
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Durvalumab + Tremelimumab + Liver Transplant
Arm Type
Experimental
Arm Description
Patients will be treated with the immunotherapy combination for up to 4 months. After a minimum 28 day washout, they will undergo locoregional therapy per institutional standards. Eventually, after a minimum 72-day washout from the end of immunotherapy, they will undergo liver transplant.
Intervention Type
Drug
Intervention Name(s)
Durvalumab
Other Intervention Name(s)
MEDI4736
Intervention Description
1500 mg IV, Q4W
Intervention Type
Drug
Intervention Name(s)
Tremelimumab
Intervention Description
300 mg IV, 1 dose on day 1 of only the first cycle
Intervention Type
Procedure
Intervention Name(s)
Liver Transplant
Intervention Description
minimum 72-day washout from the end of immunotherapy, patients will undergo liver transplant.
Primary Outcome Measure Information:
Title
Cellular rejection rates
Description
To assess the safety of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to cellular rejection rates
Time Frame
Up to 30 days post transplant
Secondary Outcome Measure Information:
Title
Adverse events during treatment, and graft loss and mortality rates
Description
To assess the safety of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to adverse events during treatment, and graft loss and mortality rates up to 30 days after transplant;
Time Frame
Treatment, and up to 30 days post transplant
Title
Radiologic responses via RECIST 1.1 and/or mRECIST
Description
To assess the efficacy of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to radiologic responses
Time Frame
Survival follow up will continue for 5 years after end of Treatment
Title
Pathologic responses via explanted liver assessment
Description
To assess the efficacy of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to Pathologic responses
Time Frame
Survival follow up will continue for 5 years after end of Treatment
Title
Recurrence-free survival and overall survival outcomes based on survival follow up reporting
Description
To assess the efficacy of immunotherapy for treatment of HCC in patients listed for a liver transplant, with respect to Survival outcomes
Time Frame
Survival follow up will continue for 5 years after end of Treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Hepatocellular carcinoma, diagnosed either by biopsy or by combination of cirrhosis and imaging criteria (contrast-enhanced CT or MRI). Tumor within UCSF criteria for transplant: either one lesion ≤6.5 cm; or up to 3 lesions, none >4.5 cm, with a total diameter ≤8 cm, with no vascular invasion and no evidence of extrahepatic disease. Patient evaluated by institutional Liver Transplant team and listed for transplant. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization. No prior therapy for HCC at any time. Age ≥18 years at the time of study entry. ECOG score of 0 or 1 Child-Pugh Score of 5, 6, or 7 Body weight >30 kg Patients must have adequate organ and marrow function as defined in protocol Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Exclusion Criteria: Extrahepatic disease. Variceal bleeding during 3 months prior to registration. Any autoimmune disease deemed a risk in the setting of immunotherapy per treating physician's judgment. Any other illness or patient condition deemed a medical or logistical barrier for protocol therapy per treating physician's judgment. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study Participation in another clinical study with an investigational product during the last 12 months Patients who have received other investigational agents previously who are no longer receiving these investigational agents may be eligible at the discretion of the PI. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. History of allogenic organ transplantation. History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the study physician Patients with celiac disease controlled by diet alone Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent History of leptomeningeal carcinomatosis History of active primary immunodeficiency Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Davendra Sohal, MD
Phone
(513) 558-2361
Email
sohalda@ucmail.uc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Christine Vollmer, MBA
Email
mccordce@ucmail.uc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Davendra Sohal, MD
Organizational Affiliation
University of Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63130
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mary Pecoraro
Phone
314-273-0884
Email
mpecoraro@wustl.edu
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christine Vollmer
Phone
513-213-3203
Email
mccordce@ucmail.uc.edu
First Name & Middle Initial & Last Name & Degree
Davendra Sohal, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Durvalumab (MEDI4736) and Tremelimumab for Hepatocellular Carcinoma in Patients Listed for a Liver Transplant

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