A phase Ib study of durvalumab (MEDI4736) tremelimumab combined with particle therapy in advanced hepatocellular carcinoma patients with macrovascular invasion

JRCT ID: jRCT2031210046

Registered date:22/04/2021

Basic Information

• Recruitment status: Suspended
• Health condition(s) or Problem(s) studied: hepatocellular carcinoma
• Date of first enrollment: 07/07/2021
• Target sample size: 15
• Study type: Interventional

Intervention(s)

administration of study drug (Durvalmab, Tremelimumab) and parforming of carbon ion radiotherapy (CIRT)

CohortA
administration of Durvalmab and parforming CIRT

CohortB
administration of Durvalmab and Tremelimumab ,and parforming CIRT

Outcome(s)

• Primary Outcome: AEs/SAEs including DLTs
• Secondary Outcome: Overall Survival (OS), Survival Rate at 6 months, Objective Response Rate (ORR), Progression Free Survival (PFS) at 6 months (in accordance with mRECIST), and if appropriate, Time to Progression (TTP).

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1.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 obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. For patients aged >=20 years and enrolling, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
2.Age >=20 years at time of study entry
3.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4.Body weight >30 kg
5.Adequate normal organ and marrow function as defined below:
Haemoglobin >=9.0 g/dL
Absolute neutrophil count (ANC) > 1500 per mm3
Platelet count >=75 x 109/L (>=75,000 per mm3)
Serum bilirubin =<3.0 x institutional upper limit of normal (ULN)
AST (SGOT)/ALT (SGPT) =<2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =<5x ULN
Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
6.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).
7.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.
8.Advanced HCC confirmed histologically or by the typical findings of a hypervascular tumor on computed tomography or angiography
9.(CohortA and CohortB) Refractory or unbearable forsystemic therapies for advanced HCC (including atezolizumab conbined with bevacizumab, sorafenib, lenvatinib)
(exclution of expantion cohort)
10.Must not be eligible for locoregional therapy for unresectable HCC. For patients who progressed after locoregional therapy for HCC, locoregional therapy must have been completed >=28 days prior to the baseline scan for the current study. Acceptable locoregional therapy for HCC are Ethanol Infusion Therapy, Radio Wave ablation Therapy, Transcatheter Arterial chemoembolization (TACE), Transcatheter arterial infusion (TAI). Hepatic Arterial Infusion Chemotherapy (HAIC) is not allowed.
11.Patients who have been diagnosed with HCC showing MVI. MVI is defined as a tumor thrombus in the major hepatic and/or portal vein branches (Vp2, Vp3, Vp4, Vv2, and Vv3) identified by imaging studies.
12.Child-Pugh A
13.At least one measurable lesion other than the MVI and feeding nodule based on mRECIST.
Must have a life expectancy of at least 12 weeks

Exclude criteria

1.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2.Participation in another clinical study with an investigational product during the last 4 weeks, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
3.Any 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.
4.Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
5.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.
6.History of allogenic organ transplantation.
7.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
8.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
9.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
10.History of leptomeningeal carcinomatosis
11.History of, or current, brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT, each preferably with IV contrast of the brain prior to study entry.
12.Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >=470 ms
13.History of active primary immunodeficiency
14.Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV). HBV positive (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA); HCV positive (presence of anti-HCV antibodies); HDV positive (presence of anti-HDV antibodies or HDV RNA), and active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice).
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:
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)
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 whilst 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 90 days after the last dose of durvalumab monotherapy or180 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 randomisation 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.
21.History of any immune checkpoint inhibitors such as anti PD-1, anti PD-L1 inhibitors, or any other agents directed to another stimulatory or co-inhibitory T-cell receptor(including atezolizumab and bevacizumab), and known no tolerance for these treatments.
22.Prior radiotherapy involving the liver.
23.Renal failure requiring hemodialysis or peritoneal dialysis
24.Any of the following cardiac diseases:
1.NYHA Class III or IV chronic heart failure
2.Current coronary artery disease or history of ischemic heart disease such as myocardial infarction within 6 months before the study
3.Serious arrhythmia (grade 3 or higher according to the CTCAE ver. 4.0: arrhythmia that cannot be controlled by oral medications or requires mechanical control).
25.Poorly controlled hypertension
26.Serious and active infection, excluding hepatitis viral infection
27.Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher. Urine dipstick result of 3+ is allowed if protein excretion is <3.5 g/24 hours.
28.Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis, or pulmonary embolism within 6 months before the start of study medication.
29.Refractory pleural effusion or ascites
30.History of hepatic encephalopathy within past 12 months
31.Oral intake impossible
32.HIV-positive
33.Pulmonary fibrosis or interstitial pneumonitis
34.Other serious complications as follows: serious mental disease or history of gastrointestinal bleeding or active hemoptysis
35.Unsatisfactory general condition for participation in the study as judge

Related Information

• Primary Sponsor: Ogasawara Sadahisa
• Source(s) of Monetary Support: AstraZeneca K.K.