| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| A type of liver cancer which may have spread to nearby tissue and is unlikely to be cured or controlled with treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with advanced liver cancer who have been previously treated with PD-1/PD-L1 Immune Checkpoint Inhibitors |
|
| 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 | 100000004864 |
|
| 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 demonstrate the objective anti-tumor activity of regorafenib in combination with pembrolizumab as a 2L treatment for advanced HCC |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate other measures of anti-tumor activity of regorafenib in combination with pembrolizumab as a 2L treatment for advanced HCC
- To evaluate safety and tolerability of regorafenib in combination with pembrolizumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- ≥18 years of age on the day of signing informed consent
- Histological or cytological confirmation of HCC or non-invasive
diagnosis of HCC as per AASLD criteria in cirrhotic participants
- Unresectable advanced HCC eligible for systemic therapy
- Participants must have progressed after only one prior line of systemic
immunotherapy treatment with an anti-PD-1/PD-L1 mAb administered
either as monotherapy or in combination with other checkpoint
inhibitors or other therapies (for prior therapy in the cohorts in the pilot
phase see Section 4.1). A wash out period of at least 28 days or 5 halflives,
whichever is shorter, must be completed for eligibility in this trial.
PD-1/PD-L1 treatment progression is defined by meeting all of the
following criteria:
a. Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb or
received PD-1/PD-L1 treatment for 8 weeks, whichever is longer.
b. Has demonstrated disease progression after PD-1/PD-L1 treatment as
defined by RECIST 1.1 (see Appendix 5, Section 10.5.1). In the absence
of rapid clinical progression, the initial evidence of RECIST 1.1 disease
progression is to be confirmed using iRECIST (see Appendix 5, section
10.5.3) by a second assessment no less than four weeks from the date of
the first documented progressive disease.
i. This determination is made by the investigator. Once progressive
disease is confirmed, the initial date of RECIST 1.1 progressive disease
documentation will be considered that date of disease progression.
ii. In cases of unequivocal clinical or radiological progression, disease
progression confirmation may not be required after documented
discussion and approval by the sponsor.
c. Progressive disease has been documented within 12 weeks from the
last dose of anti-PD-1/PD-L1 mAb.
- Participants who receive anti-PD-1 therapy as adjuvant treatment
following complete resection of liver cancer and have disease recurrence
(unresectable loco-regional disease or distant metastases) are eligible if
they progressed while on active treatment or within 6 months of
stopping anti-PD-1 therapy. This will be considered the first line of
systemic therapy.
For these participants, the following applies:
1)a second assessment to confirm disease progression beyond
recurrence is not required; and
2)they must have received at least 2 prior doses of anti-PD-1/PD-L1
mAb
- BCLC stage B or C
- Liver function status should be Child-Pugh (CP) Class A within 7 days
prior to the first dose of study intervention. CP status should be
calculated based on clinical findings and laboratory results during the
screening period.
- ECOG PS status of 0 or 1 within 7 days prior to the first dose of study
intervention.
- At least one measurable lesion by CT scan or MRI according to RECIST
1.1. Tumor lesions situated in a previously irradiated area, or in an area
subjected to other loco-regional therapy, may be considered measurable
if there has been demonstrated progression in the lesion.
- Participants with controlled (treated) hepatitis B virus (HBV) infection
will be allowed if they meet the following criteria:
• Antiviral therapy for HBV must be given for at least 4 weeks and HBV
viral load must be less than 500 IU/mL prior to first dose of study
intervention.
• Participants on active HBV therapy with viral loads under 500 IU/ml
should stay on the same therapy throughout study treatment.
• Participants who are anti-HBc (+), negative for HBsAg, negative for
anti-HBs, and have an HBV viral load under 500 IU/mL that do not
require HBV anti-viral prophylaxis.
- Provision of recent tumor tissue (as defined below) is mandatory at
screening. Exceptions will be accepted for participants with no recent
baseline tumor tissues after documented discussion and approval by the
sponsor.
• Tumor tissue obtained within 180 days of enrollment and after the last
dose of most recent anti-cancer therapy
• Or a new biopsy |
|
| E.4 | Principal exclusion criteria |
- Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes.
-Patients with disease that is suitable for local therapy administered with curative intent.
-Patients who experienced any CTCAE ≥ 3 or any other immune related toxicities that led to permanent discontinuation of treatment with immune checkpoint inhibitors in 1 L.
-Persistent proteinuria of CTCAE Grade 3 or higher.
-Diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study interventions.
- Active autoimmune disease
- History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- Any hemorrhage or bleeding event CTCAE Grade ≥ 3 within 28 days prior to the start of study medication.
- Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication.
- Ongoing infection CTCAE Grade > 2 requiring systemic therapy.
- Dual active HBV infection (HBsAg (+) and / or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
- Uncontrolled hypertension (systolic blood pressure ≥ 140 mmHg or
diastolic pressure ≥ 90 mmHg) on more than 2 separate measurements
despite optimal medical management.
- Unstable angina (angina symptoms at rest), new-onset angina (begun
within the last 3 months).
- Myocardial infarction less than 6 months before start of study
intervention.
- Pleural effusion or ascites that causes respiratory compromise (CTCAE
Grade ≥2 dyspnea).
- Patients with previous malignancies (except non-melanoma skin
cancers, and the following in situ cancers: bladder, gastric, colon,
cervical/dysplasia, melanoma, or breast) are excluded unless a complete
remission was achieved at least 3 years prior to study entry
- Known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Participants with previously treated brain
metastases may participate provided they are radiologically stable,
- Significant acute gastrointestinal disorders with diarrhea as a major
symptom
-Current evidence or suspicion of gastrointestinal perforation or fistula.
- Prior monotherapy treatment with any tyrosine kinase inhibitor in 1L.
- Prior treatment with regorafenib, in combination regimens with
immune checkpoint inhibitors.
- Transfusion of blood products within 7 days prior to signing informed
consent, or administration of colony stimulating factors within 4 weeks
prior to signing informed consent.
- Previous assignment to treatment during this study.
- Previous (at least a minimum of 28 days, or 5 half-lives of an
investigational drug before the start of study treatment, whichever is
shorter) or concomitant participation in another clinical study with investigational medicinal product(s).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) by central assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR is defined as the proportion of participants with best overall response of confirmed CR or PR. Participants for whom best overall tumor response is not CR or PR, as well as participants without any post-baseline tumor assessment will be considered non-responders.
The primary efficacy variable will be analyzed after all participants are available for efficacy. |
|
| E.5.2 | Secondary end point(s) |
•Duration of response (DOR) per RECIST 1.1 by central assessment
•Objective response rate (ORR) per RECIST 1.1 by investigator assessment
•Duration of response (DOR) per RECIST 1.1 by investigator assessment
•Number of participants with adverse events (AEs)
•Number of participants with serious adverse events (SAEs)
•Number of participants with safety-relevant changes in clinical parameters
•Number of participants with dose modification (dose interruption, dose reduction, dose discontinuation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- DOR (for PR and CR) is defined as the time (in days) from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (if death occurs before progression is documented).
- ORR is defined as the proportion of participants with best overall response of confirmed CR or PR. Participants for whom best overall tumor response is not CR or PR, as well as participants without any post-baseline tumor assessment will be considered non-responders.
-for safety objective: study duration |
|
| 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 | Yes |
| 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 | No |
| 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 | No |
| 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 | No |
| 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.8.3 |
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 | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Japan |
| Korea, Republic of |
| United States |
| France |
| Spain |
| Germany |
| Italy |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of the study (EoS) as a whole will be reached when the last visit of the last patient (LPLV) has been achieved in all participating centers |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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