Hypofractionated Radiotherapy Followed by Durvalumab With or Without Tremelimumab for Liver Cancer After Progression on PD-1 Inhibition

Advanced Hepatocellular Carcinoma Clinical Trial

Official title: Phase II Trial of Palliative Hypofractionated Radiotherapy Followed by Durvalumab (MEDI4736) With/Without Tremelimumab for Advanced Hepatocellular Carcinoma After Progression on Prior PD-1 Inhibition

Status Recruiting

Clinical Trial 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) after treatment with PD-1 inhibitor immunotherapy. 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.

Clinical Trial Description

PRIMARY OBJECTIVE:

I. Determine objective response rate (ORR) of durvalumab (D) and D + tremelimumab (T) after radiation therapy (RT) in advanced hepatocellular carcinoma (HCC) patients with progression on prior PD-1 immune checkpoint inhibitor.

SECONDARY OBJECTIVES:

I. To determine the safety of D and D + T in advanced HCC patients with progression on prior PD-1 immune checkpoint inhibitor.

II. Determine the efficacy of D and D + T in advanced HCC patients with progression on prior PD-1 immune checkpoint inhibitor.

EXPLORATORY OBJECTIVES:

I. Profile peripheral blood mononuclear cell (PBMC) immune cells and plasma samples before RT, after RT, and during D or D + T immunotherapy.

II. Explore relationship between plasma biomarkers and PBMC immune profiles, the proportion of participants with adverse events (AEs), (safety endpoint), and clinical outcomes (ORR), progression-free survival (PFS), duration of response (DOR), overall survival (OS).

III. Profile immune cells in archival pre-treatment tumor tissue for all patients and on-/post-treatment tumor samples and/or non-tumor liver tissue samples when available, and explore for relationship with safety/tolerability and clinical outcomes.

IV. Determine incidence of tumor PD-L1 expression by immunohistochemistry (IHC) in pre-treatment archival tumor samples in all patients, and in on-/post-treatment tumor samples if repeat tumor sampling is obtained for clinical indications.

V. Explore relationship between tumor PD-L1 status and clinical outcomes. VI. Explore relationship between viral hepatitis status, viral load, safety/tolerability, and clinical outcomes.

VII. Measure tumor marker alpha-fetoprotein (AFP) response to immunotherapy plus RT and explore for relationship with clinical outcomes.

VIII. Explore relationship between site of RT (liver, bone, other soft tissue), number of RT sites (1 or > 1), safety/tolerability, clinical outcomes, and changes in immune cell profiles on treatment.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients undergo standard of care hypofractionated RT over 5 fractions once daily (QD) for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive durvalumab intravenously (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.

This arm will close after the 6th participant is enrolled.

ARM II: Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with durvalumab repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who complete the first dose of tremelimumab and demonstrate clinical benefit based upon radiographic tumor regression and/or other clinical response without progression for at least 6 cycles or 6 months on treatment, whichever is shorter, and subsequently have evidence of progressive disease during the durvalumab monotherapy portion may receive a repeat dose of tremelimumab at the next scheduled cycle of treatment with durvalumab per physician discretion.

After completion of study treatment, patients are followed up every 2 months. ;

Related Conditions & MeSH terms

• Advanced Hepatocellular Carcinoma
• Carcinoma
• Carcinoma, Hepatocellular
• Stage III Hepatocellular Carcinoma AJCC v8
• 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

• NCT number: NCT04430452
• Study type: Interventional
• Source: University of California, San Francisco
• Contact: Hewitt Chang
• Phone: (415) 514-1571
• Email: Hewitt.Chang@ucsf.edu
• Status: Recruiting
• Phase: Phase 2
• Start date: February 4, 2022
• Completion date: February 28, 2027