| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-resectable hepatocellular carcinoma (HCC) |
| nicht-resezierbares Hepatozelluläres Karzinom |
|
| E.1.1.1 | Medical condition in easily understood language |
| non-resectable hepatocellular carcinoma (HCC) |
| nicht-resezierbares Hepatozelluläres Karzinom |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of Arm A and of Arm B vs. historical controls |
|
| E.2.2 | Secondary objectives of the trial |
To assess:
- the efficacy of Arm A and of Arm B
- disease-related symptoms, impacts and health-related quality of life (HRQoL) in Arm A and in Arm B
- the deterioration of liver function |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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
(European Union [EU] Data Privacy Directive) obtained from the patient/legal
representative prior to performing any protocol-related procedures, including
screening evaluations.
2. Age ≥18 years at the time of study entry
3. Body weight >30 kg.
4. Confirmed HCC based on histopathological findings from tumor tissues.
5. Must not have received prior systemic therapy for HCC.
6. Not 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.
7. Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for
locoregional therapy) or stage C (refer to Appendix C)
8. Child-Pugh Score class A. (refer to Table 8)
9. ECOG performance status of 0 or 1 at enrollment (refer to section 5.2.6)
10. Patients with HBV infection, characterized by positive hepatitis B surface antigen
(HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV
DNA (≥10 IU/ml or above the limit of detection per local or central lab standard),
must be treated with antiviral therapy, as per institutional practice, to ensure
adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to enrollment.
Patients must remain on antiviral therapy for the study duration and for 6 months
after the last dose of study medication. Patients who test positive for anti-hepatitis
B core (HBc) with undetectable HBV DNA (<10 IU/ml or under the limit of
detection per local or central lab standard) do not require anti-viral therapy prior
to enrollment. These subjects will be tested at every cycle to monitor HBV DNA
levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above
the limit of detection per local or central lab standard). HBV DNA detectable
subjects must initiate and remain on antiviral therapy for the study duration and
for 6 months after the last dose of study medication.
11. Patients with HCV infection must have confirmed diagnosis of HCV
characterized by the presence of detectable HCV RNA or anti-HCV antibody
upon enrollment (management of this disease is per local institutional practice).
12. At least 1 measurable lesion, not previously irradiated, that can be accurately
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes,
which must have a short axis ≥15 mm) with computerized tomography (CT) or
magnetic resonance imaging (MRI), and that is suitable for accurate repeated
measurements as per RECIST 1.1 guidelines. A lesion which progressed after
previous ablation or TACE could be measurable if it meets these criteria.
13. Adequate organ and marrow function, as defined below. Criteria “a,” “b,” “c,”
and “f” cannot be met with transfusions, infusions, or growth factor support
administered within 14 days of starting the first dose.
a. Hemoglobin ≥9 g/dL
b. Absolute neutrophil count ≥1500/µL
c. Platelet count ≥75000/µL
d. Total bilirubin (TBL) ≤2.0× upper limit of normal (ULN)
e. AST and ALT ≤5×ULN
f. Albumin ≥2.8 g/dL
g. International normalized ratio (INR) ≤1.6. Note: INR prolongation due to
anticoagulants for prophylaxis (e.g., atrial fibrillation) in patients without liver
cirrhosis could be exception.
h. Calculated creatinine clearance ≥50 mL/minute as determined by Cockcroft-Gault
(using actual body weight) or 24-hour urine creatinine clearance
i. Urine dipstick for proteinuria < 2+ (within 7 days prior to initiation of study
treatment), unless a subsequent 24-hour urine collection demonstrates < 1 g of
protein in 24 hours.
14. Evidence of post-menopausal status or negative serum pregnancy test
for female pre-menopausal patients. Women will be considered post-menopausal
as described in Section 3.8.
15. 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.
16. Must have a life expectancy of at least 12 weeks |
|
| E.4 | Principal exclusion criteria |
1.Involvement in the planning and/or conduct of the study
2.Previous study drug assignment in the present study
3.Concurrent enrollment in another clinical study, unless it is an observational clinical study or during the follow-up period of an interventional study
4.Participation in another clinical study with an investig. product during the last 4 W. or 5 half-lives of the respective drug/IMP, whichever is longer
5.Any unresolved toxicity for AEs (CTCAE) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria(refer to protocol)
6.Any concurrent chemotherapy, study drug, or biologic or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable
7.Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
8.Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 D. of the first dose of study drug
9. Major surgical procedure or significant traumatic injury(as defined by the Investigator)within 28 D. prior to the first dose of study drug, abdominal surgery, abdominal interventions, or significant abdominal traumatic injury within 60 D. prior to randomization or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure. Note: Local surgery of
isolated lesions for palliative intent is acceptable
10.History of allogeneic organ transplantation
11.History of hepatic encephalopathy within past 12 M. or requirement for medications to prevent or control encephalopathy
12.Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic intervention to maintain symptomatic control, within 6 M. prior to first scheduled dose. Subjects on stable doses of diuretics for ascites for ≥2 M. are eligible
13.Patients with main portal vein thrombosis on baseline imaging
14.Patient currently exhibits sympt or uncontrolled hypertension defined as DBP>90 mmHg or SBP>140 mmHg
15.Any condition interfering with swallowing pills, uncontrolled diarrhea, or other contraindication to oral therapy
16.Active or prior documented autoimmune or inflammatory disorders(refer to protocol)
17.Patients co-infected with HBV and HCV, or co-infected with HBV and HDV(refer to protocol)
18.Uncontrolled intercurrent illness, incl but not limited to(refer to protocol)
19.History of another primary malignancy except for:(Refer to protocol)
20.History of leptomeningeal carcinomatosis.
21. History of, or current, brain metastases or spinal cord compression(refer to protocol)
22. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs
23.Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
24.History of active prim. immunodeficiency
25.Known to have tested positive for HIV (positive HIV 1/2 antibodies) or active tuberculosis infection(refer to protocol)
26.Current or prior use of immunosuppressive medication within 14 D. before the first dose of study drug.The following are exceptions to this criterion(refer to protocol)
27.Receipt of live attenuated vaccine within 30 D. prior to the first dose of study drug(refer to proto.)
28.Major gastrointestinal bleeding within 4 W. prior to randomization
29.Patients with untreated or incompl treated varices with bleeding or high-risk for bleeding(refer to proto)
30.Significant vascular disease incl aortic aneurysm requiring surgical repair or peripheral arterial thrombosis with 6 M. prior to randomization
31.History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intraabdominal abscess within 6 months prior to randomization
32.History or clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding. Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure
33.Evidence of bleeding diathesis or significant coagulopathy
34.Severe, non-healing or dehisced wound, active ulcer, or untreated bone fracture
35.Current or recent (within 10 days of randomization) use of acetylsalicyclic acid or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol
36.Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose(refer to protocol)
37.Chronic daily treatment with a NSAID(refer to protocol)
38.Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab
39. Female patients who are pregnant or breastfeeding(refer to protocol)
40. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR (objective response rate) |
|
| E.5.2 | Secondary end point(s) |
• Overall survival (OS)
• Progression-free survival (PFS)
• Time to progression (TTP)
• Objective response rate acc. to BICR (ORR-BICR)
• Duration of response (DOR)
• Disease control rate (DCR)
• Proportion of patients alive at 18 months
• Proportion of patients alive at 24 months
• Progression-free survival from escalation treatment (PFS-E)
• PFS on next treatment
• TTFS (time to failure of strategy)
• Overall survival (OS)
• Progression-free survival (PFS)
• Time to progression (TTP)
• Objective response rate acc. to BICR (ORR-BICR)
• Duration of response (DOR)
• Disease control rate (DCR)
• Proportion of patients alive at 18 months
• Proportion of patients alive at 24 months
• Progression-free survival from escalation treatment (PFS-E)
• PFS on next treatment
• TTFS (time to failure of strategy)
• Overall survival (OS)
• Progression-free survival (PFS)
• Time to progression (TTP)
• Objective response rate acc. to BICR (ORR-BICR)
• Duration of response (DOR)
• Disease control rate (DCR)
• Proportion of patients alive at 18 months
• Proportion of patients alive at 24 months
• Progression-free survival from escalation treatment (PFS-E)
• PFS on next treatment
• TTFS (time to failure of strategy)
• quality of Life
• time to deterioration of liver function
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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