Phase II Trial of Durvalumab (MEDI4736) With/Without Tremelimumab for Advanced Hepatocellular Carcinoma After Palliative Hypofractionated Radiotherapy
Overview
- Phase
- Phase 2
- Intervention
- Durvalumab
- Conditions
- Advanced Hepatocellular Carcinoma
- Sponsor
- Mary Feng, MD
- Enrollment
- 21
- Locations
- 1
- Primary Endpoint
- Objective response rate (ORR)
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
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.
Detailed Description
PRIMARY OBJECTIVE: I. Determine Objective Response Rate (ORR) (per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, excluding radiotherapy (RT)-treated lesions as targets) of Durvalumab (D), and D + Tremelimumab (T) after palliative RT in advanced Hepatocellular carcinoma (HCC) participants with or without progression on prior programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of study interventions. II. Determine the efficacy of treatment interventions defined as progression-free survival (PFS), duration of response (DOR), and overall survival (OS). 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 peripheral blood and PBMC immune profiles, safety/tolerability, and clinical outcomes. 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: All participants receive 5-fraction RT as standard treatment for symptomatic or high-risk metastases and will be sequentially assigned to treatment Arm 1. Arm 1 will be closed after the 6th patient is enrolled. Subsequent participants will be enrolled directly into Arm 2 (progression on prior PD(L)-1 immune checkpoint inhibitor) or Arm 3 (no prior PD(L)-1 immune checkpoint inhibitor). After completing up to 2 years of treatment, treatment for participants with ongoing clinical benefit will be decided on a case-by-case basis and follow-ed up for survival endpoints for approximately 3 years after the first treatment.
Investigators
Mary Feng, MD
Principal Investigator
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •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)
Exclusion Criteria
- •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
- •Any other unresolved toxicity NCI CTCAE grade \>= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
Arms & Interventions
Arm I: Durvalumab monotherapy + hypofractionated radiotherapy (RT)
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.
Intervention: Durvalumab
Arm I: Durvalumab monotherapy + hypofractionated radiotherapy (RT)
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.
Intervention: Hypofractionated Radiation Therapy
Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors
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.
Intervention: Durvalumab
Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors
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.
Intervention: Hypofractionated Radiation Therapy
Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors
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.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Objective response rate (ORR)
Time Frame: Up to 2 years
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
Secondary Outcomes
- Median Progression-free survival(Up to 3 years)
- Proportion of participants with reported treatment-related adverse events(Up to 2 years)
- Median Duration of overall Complete Response (DOSD)(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 Overall survival (OS)(Up to 3 years)