Trial Title:
Deep, Multi-omics Phenotyping to Predict Response, Resistance and Recurrence to Adjuvant Atezolizumab Plus Bevacizumab in Resected Hepatocellular Carcinoma
NCT ID:
NCT05516628
Condition:
Hepatocellular Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Recurrence
Bevacizumab
Atezolizumab
Conditions: Keywords:
Hepatocellular Carcinoma (HCC)
Adjuvant Atezolizumab
Adjuvant Bevacizumab
Biomarkers
Multiomics profiles
Spatial TME profiles
Surgically resected HCC
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Surgical Resection
Description:
Resection of Primary Hepatocellular Cancer Tumour.
Arm group label:
Surgery followed by Adjuvant Atezolizumab-Bevacizumab Therapy every 3-weekly
Intervention type:
Drug
Intervention name:
Adjuvant Atezolizumab-Bevacizumab Therapy
Description:
Patient receives adjuvant Atezolizumab plus Bevacizumab every 3-weekly for a year
following resection of hepatocellular cancer tumour.
Arm group label:
Surgery followed by Adjuvant Atezolizumab-Bevacizumab Therapy every 3-weekly
Summary:
Hepatocellular carcinoma (HCC) is the 7th most common cancer worldwide but is the 4th
deadliest, because diagnosis tend to be late and current systemic therapies are poorly
efficacious. Within the same tumour, different parts of the HCC can belong to separate
molecular sub-groups. In addition, there is currently no validated predictive biomarkers
to help clinicians select the best therapy for an individual patient. This challenge
poses an urgent, unmet clinical need.
To address this, the multi-disciplinary research program Precision Medicine in Liver
Cancer across an Asia-Pacific Network (PLANet 1.0) was conceptualized and successfully
conducted from 2016-22. The program uncovered novel insights into the highly
heterogeneous molecular landscape of HCC and novel mechanisms, including how HCC reverts
to fetal forms to escape the body's immunological defence.
These investigations will be continued in PLANet 2.0 and in this new phase, the research
team will investigate patients receiving best-in-class therapeutics in 2
investigator-initiated clinical studies (AHCC12 and AHCC13), including Atezolizumab plus
Bevacizumab (Atezo+Bev) and Yttrium-90, which allows the research team to collect
longitudinal, before and after treatment biosamples and clinical data. These clinical
studies will serve as proof-of-concept to the study team's translational findings and
allow it to uncover predictive biomarkers which will help clinicians to institute more
efficacious and personalized treatment in the future. The research team comprises of
experts in different complementary fields (epigenomics, genomics, immunomics,
metabolomics, proteomics, clinical science and data science) and across different
institutions. This allows the team to adopt an integrative approach in understanding the
landscape of the HCC tumour micro-environment and biomarkers co-localisation, and their
role in tumour evolution and therapeutic response. By adopting a wide spectrum of
converging investigations, PLANet 2.0 will identify and validate biomarkers that
correlate with clinical outcomes (response, resistance and recurrence).
Detailed description:
This is a clinical translational study on a prospective, interventional clinical cohort
(defined as the AHCC12 study). Patient will receive adjuvant Atezolizumab plus
Bevacizumab every 3-weekly for a year following surgery. Serially collected biosamples
will be deeply-phenotyped and correlated with treatment outcomes (recurrence vs
non-recurrence).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patient is willing, able and mentally competent to provide written informed consent
prior to any testing undertaken for this study protocol, including screening tests
and evaluations that are not considered to be part of the patient's routine care.
2. Male and female patients, age 21 to 90 at the time of signature of the informed
consent form.
3. Patient is able to comply with scheduled visits, assessments and other study
procedures.
4. Patient diagnosed with HCC or its histological variants who has undergone a
resection within 4-12 weeks prior to Day 1 of Cycle 1.
- Multimodality treatment is not permitted, for example resection and ablation
- Combination treatment is not permitted.
5. Patient has clinically AND histologically proven HCC after liver resection as
described below:
- Patients must have documented histological HCC confirmation of negative
surgical margins (R0) which is documented in a pathology report (patients with
microscopically positive [R1] or grossly positive [R2] resection margins or
unknown margins will be excluded from the study).
- Patients must have disease-free status documented within 4 weeks prior to Day 1
of Cycle 1 by a complete physical examination and radiographic images, with no
subsequent evidence of residual or recurrent disease prior to Day 1 of Cycle 1.
A complete set of baseline (post-resection) radiographic images and
accompanying report must be available prior to Day 1 of Cycle 1.
6. Patient has an absence of major macrovascular (gross vascular) invasion of the
portal vein (Vp3 or Vp4) or major macrovascular invasion in the inferior vena cava
(Vv3).
7. Patient has an absence of extrahepatic spread as confirmed by CT or MRI scan of the
chest, abdomen, pelvis, and head prior to and following resection . If head scan was
not performed prior to resection, this must be performed after resection.
8. Patient has a full recovery from surgical resection within 4 weeks prior to Day 1 of
Cycle 1.
9. Patient is at high risk for HCC recurrence after resection as defined in Table 1:
- Up to three tumours, with largest tumour > 5 cm regardless of vascular invasion
(microvascular invasion or macrovascular invasion of the portal vein - Vp1/Vp2
or hepatic vein - Vv1/Vv2), or poor tumour differentiation (Grade 3 or 4)
- Up to three tumours, with largest tumour ≤ 5cm with vascular invasion
(microvascular invasion or macrovascular invasion of the portal vein - Vp1/Vp2
or hepatic vein - Vv1/Vv2) and/or poor tumour differentiation (Grade 3 or 4)
- Four or more tumours, with largest tumour ≤ 5 cm regardless of microvascular
invasion (microvascular invasion or macrovascular invasion of the portal vein -
Vp1/Vp2 or hepatic vein - Vv1/Vv2) or poor tumour differentiation (Grade 3 or
4)
- In the event that the pathology and the pre- resection radiology report are
discordant with regards to tumour size and number, the modality demonstrating
the largest tumour size and number should be used to determine high risk
features. Pathological findings should be used to assess for microvascular
invasion and/or poor tumour differentiation. If macrovascular invasion of Vp1
or Vp2 or Vv1 or Vv2 is detected on either the pre-operative CT/MRI scan or the
pathology report, this should be a high risk feature
10. Patient has baseline tumour tissue samples that meet the following criteria:
- Good DNA/RNA quality (Refer to Biosamples Collection Protocol)
- High tumour viability (Refer to Biosamples Collection Protocol)
11. Patient is known to be negative for the Human Immunodeficiency Virus (HIV).
12. Patient with documented virology status of hepatitis, as confirmed by screening HBV
and HCV tests
- For patients with active HBV: HBV DNA < 500 IU/mL during screening, initiation
of anti-HBV treatment at least 14 days prior to Day 1 of Cycle 1 and
willingness to continue anti-HBV treatment during the study (per local standard
of care; e.g., entecavir). Patients with HBV DNA > 500 IU/mL should be
continued on antiviral treatment to obtain HBV DNA < 500 IU/mL before Day 1 of
Cycle 1. Antiviral treatment shall continue throughout the entire Atezo+Bev
treatment phase.
- Patients with HCV, either with resolved infection (as evidenced by detectable
antibody) or chronic infection (as evidenced by detectable HCV RNA), are
eligible
- For patients with detectable HCV RNA and for whom HCV treatment is deemed
appropriate by the investigator, treatment should begin no sooner than 6 months
following resection consistent with AASLD guidelines
13. Patient is willing to receive an esophagogastroduodenoscopy, either before resection
as part of pre-procedure work-up or following resection, and assessment and
treatment of varices of all sizes per local standard of care prior to Day 1 of Cycle
1.
14. Patient is willing to receive an electrocardiogram, either before resection as part
of pre-procedure work-up or following resection, prior to Day 1 of Cycle 1.
15. Patient with Child-Pugh A (up to 6 points) without clinical ascites before surgery
16. Patient with ECOG performance status 0-1.
17. Patient has adequate hematological, renal and hepatic function, defined by the
following laboratory test results, obtained within 7 days prior to Day 1 of Cycle 1
unless otherwise specified:
- AST, ALT, and ALP ≤ 5 × ULN
- Serum bilirubin ≤ 3 × ULN
- Albumin ≥ 28 g/L (2.8 g/dL)
- Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min (calculated
using the Cockcroft-Gault formula)
- Hemoglobin ≥ 90 g/L (9 g/dL) Patients may be transfused to meet this criterion.
- Platelet count ≥ 75 × 10**9/L (75,000/µL) without transfusion
- Lymphocyte count ≥ 0.5 × 10**9/L (500/µL)
- ANC ≥ 1.5 × 10**9/L (1500/µL) without granulocyte colony-stimulating factor
support
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2 × ULN
- Urine dipstick for proteinuria < 2 + (within 7 days prior to Day 1 of Cycle 1)
Patients discovered to have ≥ 2 + proteinuria on dipstick urinalysis at
baseline should undergo a 24-hour urine collection (or an alternative method
such as protein:creatinine ratio, per local guidance) and must demonstrate < 1
g of protein in 24 hours.
18. Patient is estimated to have a life expectancy of at least 3 months without any
active treatment.
19. Patient is deemed suitable for protocol treatment as determined by clinical
assessment undertaken by the site Investigator.
20. (For female patients) Patient is either postmenopausal or, if premenopausal, must
have a negative pregnancy test and agree to use two forms of contraception if
sexually active during the treatment period, for at least 5 months after the last
dose of atezolizumab and 6 months after the last dose of bevacizumab.
21. (For male patients) Patient is surgically sterile, or if sexually active and having
a pre-menopausal female partner, must be using an acceptable form of contraception
during the treatment period and for 6 months after the last dose of bevacizumab.
Exclusion Criteria:
1. Patient is unable to provide informed consent or refuse blood taking.
2. Patient has evidence of residual, recurrent, or metastatic disease prior to
initiation of treatment.
3. Patient has clinically significant ascites or any other clinical signs of liver
failure on physical examination at time of enrolment.
4. Patient has a history of hepatic encephalopathy.
5. Patient has a bleeding event due to untreated or incompletely treated esophageal
and/or gastric varices prior to Day 1 of Cycle 1.
6. Patient has active or history of autoimmune disease or immune deficiency, including,
but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome,
Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
- Rash must cover < 10% of body surface area.
- Disease is well controlled at baseline and requires only low-potency
topical corticosteroids.
- There is no occurrence of acute exacerbations of the underlying condition
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors, or high-potency or oral
corticosteroids within the 12 months prior to Day 1 of Cycle 1.
7. Patient has a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or
evidence of active pneumonitis on chest CT scan at screening.
8. Patient has significant cardiovascular disease (such as New York Heart Association
Class II or greater cardiac disease, myocardial infarction, or cerebrovascular
accident) within 3 months prior to Day 1 of Cycle 1, unstable arrhythmia, or
unstable angina
9. Patient has a history of malignancy other than HCC within 5 years prior to
screening, with the exception of malignancies with a negligible risk of metastasis
or death (e.g., 5-year overall survival [OS] rate > 90%), such as adequately treated
carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate
cancer, ductal carcinoma in situ, or Stage I uterine cancer. Effectively treated
malignancies,including HCC that have been in remission for over 5 years can be
allowed as they are highly likely to have been cured.
10. Patient has active tuberculosis at screening
11. Patient has a severe infection within 4 weeks prior to Day 1 of Cycle 1, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia, or any active infection that in the opinion of the investigator,
could impact patient safety
12. Patient has received treatment with therapeutic oral or IV antibiotics within 2
weeks prior to Day 1 of Cycle 1
• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract
infection or chronic obstructive pulmonary disease exacerbation) are eligible for
the study.
13. Patient has prior allogeneic stem cell or solid organ transplantation
14. Patient is on the waiting list for liver transplantation
15. Patient has any other disease, metabolic dysfunction, physical examination finding,
or clinical laboratory finding that contraindicates the use of an investigational
drug, may affect the interpretation of the results, or may render the patient at
high risk from treatment complications
16. Patient has a co-infection with HBV and HCV or Hepatitis D viral infection
• Patients with a history of HCV infection but who are negative for HCV RNA by
polymerase chain reaction will be considered to be negative for HCV infection.
17. Patient has clinically significant uncontrolled or symptomatic hypercalcemia
(ionized calcium > 1.5 mmol/L, calcium > 12mg/dL, or corrected serum calcium > ULN)
18. Patient has a history of severe allergic anaphylactic reactions to chimeric or
humanized antibodies or fusion proteins
19. Patient has known hypersensitivity to Chinese hamster ovary cell products or to any
component of the atezolizumab or bevacizumab formulations
20. Patient has received any treatment for HCC prior to resection, including previous
liver resection, systemic therapy (including investigational agents) and
locoregional therapy (e.g. RFA, TACE, SIRT), radiotherapy, immunotherapy,
chemotherapy or neo-adjuvant chemotherapy other than the planned surgery. However,
patient who has received previous HCC resection more than 5 years ago is deemed to
have a de-novo liver tumour and therefore can be included.
- Prior use of herbal therapies or traditional Chinese medicines with anti-cancer
activity included in the label is allowed, but such therapies must be
discontinued at least 7 days prior to Day 1 of Cycle 1 and are prohibited
during the study.
- Portal vein embolization used to increase the functional liver remnant prior to
surgery is permitted.
21. Patient has received or plans to receive treatment with a live, attenuated vaccine
within 4 weeks prior to Day 1 of Cycle 1, or anticipation of need for such a vaccine
during atezolizumab treatment or within 5 months after the final dose of
atezolizumab
22. Patient has received prior treatment with investigational therapy within 4 weeks
prior to Day 1 of Cycle 1
23. Patient has prior treatment with CD137 agonists or immune checkpoint blockade
therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
24. Patient has received prior treatment with systemic immunostimulatory agents
(including, but not limited to, interferon and interleukin-2) within 4 weeks or 5
drug elimination half-lives (whichever is longer) prior to Day 1 of Cycle 1
25. Patient has received prior treatment with systemic immunosuppressive medication
(including, but not limited to, corticosteroids, cyclophosphamide, azathioprine,
methotrexate, thalidomide, and anti-tumour necrosis factor-α [TNF-α] agents) within
2 weeks prior to Day 1 of Cycle 1, or anticipation of need for systemic
immunosuppressive medication during study treatment, with the following exceptions:
- Patients who received acute, low-dose systemic immunosuppressant medication or
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are eligible.
- Patients who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
are eligible for the study.
26. Patient has inadequately controlled arterial hypertension (defined as systolic blood
pressure [BP] > 150 mmHg and/or diastolic BP > 100 mmHg), based on an average of at
least three BP readings at two or more sessions
• Anti-hypertensive therapy to achieve these parameters is allowed.
27. Patient has a history of hypertensive crisis or hypertensive encephalopathy
28. Patient has significant vascular disease (e.g., aortic aneurysm requiring surgical
repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of
Cycle 1
29. Patient has a history of hemoptysis (≥ 2.5 mL of bright red blood per episode)
within 1 month prior to Day 1 of Cycle 1
30. Patient has evidence of bleeding diathesis or significant coagulopathy (in the
absence of therapeutic anticoagulation)
31. Current or recent (within 10 days prior to Day 1 of Cycle 1) use of full-dose oral
or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to
prophylactic) purpose
- Prophylactic anticoagulation for the patency of venous access devices is
allowed provided the activity of the agent results in an INR < 1.5 × ULN and
aPTT is within normal limits (according to institutional standards) within 14
days prior to Day 1 of Cycle 1.
- Prophylactic use of low-molecular-weight heparin (LWMH; i.e., enoxaparin 40
mg/day) is allowed. However, the use of direct oral anticoagulant therapies
such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due
to bleeding risk. Benefits and risks should be assessed and caution exercised
for use of direct oral anticoagulants. The investigator should consider
switching to other approved anticoagulants due to the risk of upper GI bleeding
in patients with HCC.
32. Patient has received a core biopsy or other minor surgical procedure, excluding
placement of a vascular access device, within 3 days prior to Day 1 of Cycle 1
33. Patient has a history of GI fistula, GI perforation, or intra-abdominal abscess
within 6 months prior to Day 1 of Cycle 1
34. Patient has evidence of abdominal free air that is not explained by paracentesis or
recent surgical procedure
35. Patient has a serious, non-healing or dehiscing wound, active ulcer, or untreated
bone fracture
36. Patient is receiving or plans to receive a major surgical procedure within 4 weeks
prior to Day 1 of Cycle 1 or anticipation of need for a major surgical procedure
during the study
37. Patient has a history of clinically significant intra-abdominal inflammatory process
within 6 months prior to Day 1 of Cycle 1, including, but not limited to, peptic
ulcer disease, diverticulitis, or colitis
38. (For female patients) Patient is pregnant or breastfeeding, or intending to become
pregnant during the study or within 5 months after the final dose of atezolizumab or
within 6 months after the final dose of bevacizumab
- Women of childbearing potential must have a negative serum pregnancy test
result within 14 days prior to Day 1 of Cycle 1.
Gender:
All
Minimum age:
21 Years
Maximum age:
90 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National University Hospital Singapore
Address:
City:
Singapore
Zip:
119074
Country:
Singapore
Status:
Recruiting
Contact:
Last name:
Cheng Ean CHEE, MD
Phone:
+65 6779 5555
Email:
mdccce@nus.edu.sg
Facility:
Name:
National Cancer Centre Singapore
Address:
City:
Singapore
Zip:
169610
Country:
Singapore
Status:
Recruiting
Contact:
Last name:
Han Chong TOH, MD
Phone:
+65 6436 8000
Email:
toh.han.chong@singhealth.com.sg
Facility:
Name:
Singapore General Hospital
Address:
City:
Singapore
Zip:
169856
Country:
Singapore
Status:
Recruiting
Contact:
Last name:
Brian GOH, MD
Phone:
+65 6326 5440
Email:
brian.goh@singhealth.com.sg
Facility:
Name:
Tan Tock Seng Hospital
Address:
City:
Singapore
Zip:
308433
Country:
Singapore
Status:
Recruiting
Contact:
Last name:
Jens SAMOL, MD
Phone:
+65 6359 6555
Email:
Jens_SAMOL@ttsh.com.sg
Facility:
Name:
Changi General Hospital
Address:
City:
Singapore
Zip:
529889
Country:
Singapore
Status:
Recruiting
Contact:
Last name:
Adrian CHIOW, MD
Phone:
+65 6936 6754
Email:
adrian.chiow.k.h@singhealth.com.sg
Facility:
Name:
Sengkang General Hospital
Address:
City:
Singapore
Zip:
544886
Country:
Singapore
Status:
Recruiting
Contact:
Last name:
Juinn Huar KAM, MD
Phone:
+65 6930 5327
Email:
kam.juinn.huar@singhealth.com.sg
Start date:
February 28, 2023
Completion date:
March 2027
Lead sponsor:
Agency:
National Cancer Centre, Singapore
Agency class:
Other
Collaborator:
Agency:
Singapore General Hospital
Agency class:
Other
Collaborator:
Agency:
National University Hospital, Singapore
Agency class:
Other
Collaborator:
Agency:
Changi General Hospital
Agency class:
Other
Collaborator:
Agency:
Sengkang General Hospital
Agency class:
Other
Collaborator:
Agency:
Tan Tock Seng Hospital
Agency class:
Other
Collaborator:
Agency:
Singapore Clinical Research Institute
Agency class:
Other
Collaborator:
Agency:
Genome Institute of Singapore
Agency class:
Other
Collaborator:
Agency:
Institute of Molecular and Cell Biology of Singapore
Agency class:
Other
Collaborator:
Agency:
Cancer Science Institute of Singapore
Agency class:
Other
Collaborator:
Agency:
Duke-NUS Graduate Medical School
Agency class:
Other
Collaborator:
Agency:
Singapore Phenome Centre
Agency class:
Other
Collaborator:
Agency:
Nanyang Technological University
Agency class:
Other
Collaborator:
Agency:
NMRC OF-LCG (OFLCG21Jun-0016)
Agency class:
Other
Source:
National Cancer Centre, Singapore
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05516628
