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.
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.
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) with last dose of PD-(L)1 inhibitor at least 4 weeks but within 6
months before enrollment
- 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 or B7
- 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
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count >= 1,500/microliter (mcL)
- Platelet count >= 75,000/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 > 40 mL/min by Cockcroft Gault formula
- No contraindication to immune checkpoint inhibitor immunotherapy
- No contraindication to RT
- Life expectancy of >= 12 weeks
- Body weight > 30 kg (66.1 pounds)
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy)
- Women >= 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses > 1 year ago, had
chemotherapy-induced menopause with last menses > 1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy)
- Women of childbearing potential and men must agree to use adequate contraception from
the time of screening through the duration of study participation and for at least 6
months after receiving combination of durvalumab plus tremelimumab and 3 months after
last dose of durvalumab
- 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
- 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. Written informed consent and any locally required authorization (e.g.,
Health Insurance Portability and Accountability Act in the United States [US])
obtained from the patient/legal representative prior to performing any
protocol-related procedures, including screening evaluations
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:
- Must not have experienced 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
- All AEs while receiving prior immunotherapy must have resolved to grade =< 1 or
resolved to baseline prior to screening for this study, 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
- Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of a
grade >= 3 AE if previously re-challenged, and not 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
- 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
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients with celiac disease controlled by diet alone
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- 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 another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease >= 2
years before the first dose of investigational product (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
- 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 tuberculosis (TB) testing
in line with local practice)
- Known human immunodeficiency virus (HIV) infection
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab/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., computed
tomography [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 whilst 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 through the duration of study participation and for at least 6 months after
receiving combination of durvalumab plus tremelimumab and 3 months after last dose of
durvalumab
- Known allergy or hypersensitivity to IP, 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
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Any condition which, in the investigator's opinion, makes the subject unsuitable for
trial participation
