Durvalumab With/Without Tremelimumab After Palliative Hypofractionated Radiotherapy for Hepatocellular Carcinoma

NCT04430452 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 194522NCI-2020-03671
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well standard of care hypofractionated radiation therapy followed by durvalumab with or without tremelimumab works in treating patients with hepatocellular cancer (liver cancer) that has spread to other places in the body (advanced) and that is growing, spreading, or getting worse (progressing). In some patients, cancer cells and immune cells start to express signals that stop the body's immune system from killing the cancer. New drugs being developed, such as durvalumab and tremelimumab, are designed to target and block these signals and may help increase the immune response to prevent or slow down cancer growth. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may help the immune system work even better. Giving durvalumab with or without tremelimumab after radiation therapy may work better than radiation therapy alone in treating patients with liver cancer.

Conditions

Stage IIIA Hepatocellular Carcinoma AJCC v8; Stage IIIB Hepatocellular Carcinoma AJCC v8; Stage IV Hepatocellular Carcinoma AJCC v8; Stage IVA Hepatocellular Carcinoma AJCC v8; Stage IVB Hepatocellular Carcinoma AJCC v8; Stage III Hepatocellular Carcinoma AJCC v8; Advanced Hepatocellular Carcinoma

Keywords

Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR)

  Response is defined per Response Evaluation Criteria in Solid Tumors 1.1 as a complete response (CR) or Partial Response (PR) (CR+PR=ORR) excluding radiation therapy-treated lesions. Response will be assessed after participants complete 5 fractions of standard palliative radiotherapy (RT). Proportion of participants with a confirmed response and corresponding exact confidence intervals will be reported by Arm. Participants with unevaluable or unknown response status will be considered non-responders

  Up to 2 years

Secondary Outcomes (6)

• Proportion of participants with reported treatment-related adverse events

  Up to 2 years

• Median Duration of overall response (DOR)

  Up to 2 years

• Median Duration of overall Complete Response (DOCR)

  Up to 2 years

• Median Duration of overall Complete Response (DOSD)

  Up to 2 years

• Median Overall survival (OS)

  Up to 3 years

Study Arms (3)

Arm I: Durvalumab monotherapy + hypofractionated radiotherapy (RT)

EXPERIMENTAL

Participants undergo standard of care RT over 5 fractions once a day (QD) for 5 days. Within 3-10 days after completion of RT, participants receive durvalumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Biological: Durvalumab; Radiation: Hypofractionated Radiation Therapy

Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors

EXPERIMENTAL

Participants with progression on prior PD-L1 immune checkpoint inhibitor undergo standard of care hypofractionated radiotherapy (RT) over 5 fractions QD for 5 days and then receive a single, fixed dose of tremelimumab (300 mg IV) administered on Day 1, in combination with a fixed dose of durvalumab (1500 mg IV) every 28 days (+/-4 days for Cycles 2+), initiated within 3-10 days of completing RT, until confirmed radiographic progression or other criteria for discontinuation.

Biological: Durvalumab; Radiation: Hypofractionated Radiation Therapy; Biological: Tremelimumab

Arm III: No previous PD-L1 checkpoint inhibitor therapy

EXPERIMENTAL

Participants without prior PD-L1 immune checkpoint inhibitor therapy undergo standard of care hypofractionated radiotherapy (RT) over 5 fractions QD for 5 days and then receive a single fixed dose of tremelimumab (300 mg IV) administered on Day 1, in combination with durvalumab at fixed dose of 1500 mg IV every 28 days (+/-4 days for Cycles 2+), initiated within 3-10 days of completing RT, until confirmed radiographic progression or other criteria for discontinuation.

Interventions

Durvalumab BIOLOGICAL

Given IV

Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736

Arm I: Durvalumab monotherapy + hypofractionated radiotherapy (RT); Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors

Hypofractionated Radiation Therapy RADIATION

Undergo hypofractionated RT

Also known as: Hypofractionated Radiotherapy, hypofractionation

Arm I: Durvalumab monotherapy + hypofractionated radiotherapy (RT); Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors

Tremelimumab BIOLOGICAL

Given IV

Also known as: Anti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, Ticilimumab

Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically-diagnosed HCC with progression during or after prior PD-(L)1 checkpoint inhibitor immunotherapy (e.g., nivolumab and/or pembrolizumab or atezolizumab; prior durvalumab excluded), or without prior PD-(L)1 checkpoint inhibitor immunotherapy.
• a. For patients without prior histologic or cytologic diagnosis, radiographic diagnosis is allowed provided patients meet American Association for the Study of Liver Diseases (AASLD) criteria for radiographic diagnosis.
• At least 1 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1-measurable tumor present which has not received RT or other local therapy prior to enrollment.
• Clinical indication for RT to any site (e.g. painful primary or metastatic tumor, local complication risk such as impending biliary or vascular obstruction).
• Child Pugh score of A, B7, or B8 provided other liver function criteria are met.
• Eastern Cooperative Oncology Group (ECOG) 0 or 1
• Appropriate antiviral therapy for hepatitis B virus (HBV) according to institutional standard of care with HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) \< 2000 IU/mL.
• Adequate organ function as defined below:
• Hemoglobin \>= 9.0 g/dL
• Absolute neutrophil count \>= 1,200/microliter (mcL)
• Platelet count \>= 60,000/mcL
• Serum bilirubin =\< 1.5 x institutional upper limit of normal. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
• Aspartate aminotransferase (AST) =\< 2.5 x institutional upper limit of normal unless liver metastases are present in which case it can be =\< 5 x upper limit of normal (ULN)
• International normalized ratio (INR) \< 1.5
• Creatinine clearance \> 30 mL/min by Cockcroft Gault formula.

You may not qualify if:

• Prior radiotherapy to tumor sites requiring RT which could compromise safety of additional treatments.
• Prior radiotherapy to more than 30% of bone marrow or to a wide field within 4 weeks of the first study treatment.
• Prior treatment with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or PD-L1 inhibitor.
• History of allogenic organ transplantation.
• On prior PD-1 inhibitor immunotherapy:
• Any immune-related adverse events with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 grade \>= 3 on any prior immunotherapy or toxicity that led to permanent discontinuation of prior immunotherapy.
• Any AEs while receiving prior immunotherapy not resolved to grade =\< 1 or resolved to baseline, with the exception of patients with endocrine AE of grade =\< 2, who are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic
• Required the use of additional immunosuppression other than corticosteroids for the management of an AE, experienced recurrence of a grade \>= 3 AE if previously re-challenged, and currently require maintenance doses of \> 10 mg prednisone or equivalent per day
• Major surgery, liver-directed therapy, or any other anticancer therapy (e.g. chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) less than 4 weeks prior to enrollment
• Patients with grade \>= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the study physician
• Concurrent enrollment in another interventional clinical study, except only in the follow-up period of that study.
• Participation in another interventional clinical study with an investigational product during the past 4 weeks except only in the follow-up period of that study.
• 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

Sponsors & Collaborators

• Mary Feng, MD: lead
• AstraZeneca: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

durvalumab; Immunoglobulin G; Disulfides; Radiation Dose Hypofractionation; tremelimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals; Dose Fractionation, Radiation; Radiotherapy Dosage; Radiotherapy; Therapeutics

Study Officials

• Mary Feng, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Luchia Andemicael

CONTACT

(415) 530-9814; Luchia.Andemicael@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 10, 2020
• First Posted: June 12, 2020
• Study Start: February 4, 2022
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2029
• Last Updated: December 8, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)