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JOURNAL ONKOLOGIE – STUDIE

The ABC-HCC Trial: Atezolizumab Plus Bevacizumab vs. Transarterial Chemoembolization (TACE) in Intermediate-stage HepatoCellular Carcinoma

Noch nicht rekrutierend

NCT-Nummer:
NCT04803994

Studienbeginn:
Juni 2021

Letztes Update:
02.06.2021

Wirkstoff:
Atezolizumab, Bevacizumab

Indikation (Clinical Trials):
Carcinoma, Carcinoma, Hepatocellular

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Collaborator:
-

Studienleiter

Salah Eddin Al-Batran, Prof. Dr.
Study Director
Institut für Klinische Krebsforschung IKF GmbH, Frankfurt, Germany
Peter Galle, Prof. Dr.
Principal Investigator
Universitätsmedizin Mainz, Germany
Jordi Bruix, Prof. Dr.
Principal Investigator
Barcelona Clinic Liver Cancer, Universitat de Barcelona, Spain

Kontakt

Studienlocations
(2 von 2)

Darmkrebszentrum der Universitätsmedizin Mainz
Langenbeckstraße 1
55131 Mainz
Deutschland» Google-Maps
Barcelona Clinic Liver Cancer, Universitat de Bracelona
08036 Barcelona
Spain» Google-Maps

Studien-Informationen

Detailed Description:

The main purpose of this phase IIIb study is to test the efficacy and safety of atezolizumab

in combination with bevacizumab compared to TACE in patients with intermediate stage liver

cancer.

Primary efficacy objective is to assess the efficacy of atezolizumab in combination with

bevacizumab compared to TACE in patients with intermediate stage liver cancer.

The secondary efficacy objective is to further characterize the responses obtained with the

respective therapeutic strategy and to assess the impact of each therapeutic strategy on

liver function over time.

Furthermore the objective is to evaluate the safety and tolerability of each therapeutic

strategy and their respective impact on Quality of Life and to identify prognostic and

predictive angiogenic and immune related biomarkers (tissue and circulating) for study

endpoints.

This is a Phase IIIb, randomised, multicenter, open-label study. Approximately 434 patients

suffering from intermediate-stage hepatocellular carcinoma will be enrolled in this trial.

Patients will be recruited from up to 60 sites in 10 different countries.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Signed Informed Consent Form available

2. Patients ≥ 18 years of age at time of signing Informed Consent Form (for Taiwan: ≥ 20

years)

3. Confirmed hepatocellular carcinoma diagnosis based on histopathological findings from

tumor tissue or typical diagnostic imaging on dynamic CT or MRI according to AASLD

criteria.

4. Disease not amenable to curative surgery or transplantation or curative ablation BUT

disease amenable to TACE

5. Extent of disease according to the following parameters:

- Multifocal HCC beyond Milan criteria (i.e. >3 lesions of any size OR ≥2 lesions

with at least one of them being ≥ 3cm)

- More than one untreated HCC untreated nodule > 10 mm showing arterial

hyperenhancement

- No massive multinodular pattern preventing adequate TACE

- No tumor of a diffuse infiltrative HCC type

- Patent portal vein flow

- No portal vein invasion/thrombosis (even segmental) on baseline/eligibility

imaging

- No extrahepatic disease

6. Patients with recurrence after resection/ablation are eligible if initially having

achieved complete response AND recurrence developed within 2 years (i.e. ≤730 days)

before trial inclusion AND if ≥ 2 untreated nodules with > 10 mm with arterial

enhancement are present at timepoint of trial inclusion.

7. Child-Pugh score class A without ascites requiring more than 100 mg of

spironolactone/day (see exclusion criteria) at enrollment.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 at enrollment.

9. Adequate organ and bone marrow function

10. Life expectancy of ≥ 3 months

11. The following laboratory values obtained less than or equal to 7 days prior to

randomization.

- Platelet count ≥ 75,000 per µL (75x109/L)

- Hemoglobin ≥ 9.0 g per dL [transfusion allowed]

- Total bilirubin ≤ 2.0 x the upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN

- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCL) ≥ 50mL/min

(calculated using the Cockcroft-Gault formula)

- Urine dipstick for proteinuria ≤ 2+ (within 7 days prior to initiation of study

treatment) Patients discovered to have ≥2+ proteinuria on dipstick urinalysis at

baseline should undergo a 24-hour urine collection and must demonstrate <1 g of

protein in 24 hours

- INR or aPTT ≤ 1.5 x ULN (therapeutic anticoagulation prohibited - see exclusion

criterion #13; prophylactic anticoagulation permitted, e.g. LMW heparin, ASS up

to 250mg/qd)

- Alkaline phosphatase ≤ 2.5 x ULN

- Absolute neutrophil count (ANC) ≥ 1.500 per µL (1.5x109/L) without granulocyte

colony-stimulating factor support

- Serum albumin ≥ 2.8 g per dL (28g/L)

12. Pre-treatment tumor tissue sample (if available)

- If tumor tissue is available, a formalin-fixed, paraffin-embedded (FFPE) tumor

specimen in a paraffin block (preferred) or approximately 10 to 15 slides

containing unstained, freshly cut, serial sections should be submitted along with

an associated pathology report.

- If FFPE specimens described above are not available, any type of specimens

(including fine-needle aspiration, cell pellet specimens [e.g., from pleural

effusion], and lavage samples) are also acceptable. This specimen should be

accompanied by the associated pathology report.

- If tumor tissue is not available (e.g., patient has never undergone biopsy or

tissue depleted because of prior diagnostic testing), patients are still

eligible.

13. Negative serum pregnancy test done lesser than or equal to 7 days prior to

randomization, for females of childbearing potential only.

14. No presence of untreated or incompletely treated varices with bleeding or high-risk

for bleeding: Availability of esophagogastroduodenoscopy (not older than 6 months) in

which all size of varices (small to large) had been assessed and varices were treated

per local standard of care prior to enrollment.

15. Absence of other severe comorbidities

16. Resolution of any acute, clinically significant treatment-related adverse events from

prior therapy/procedure to Grade ≤ 1 prior to study entry, with the exception of

alopecia.

17. For patients with active hepatitis B virus (HBV):

- HBV DNA ≤500 IU/mL obtained within 28 days prior to initiation of study

treatment, AND

- Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of

14 days prior to study entry and willingness to continue treatment for the length

of the study.

18. For patients with active hepatitis C virus (HCV):

- Patients positive for hepatitis C virus (HCV) antibody are eligible, also if

polymerase chain reaction testing is positive for HCV ribonucleic acid (RNA).

- However, anti-viral therapy against HCV is only allowed prior to trial but not

during the trial.

19. For women of childbearing potential: agreement to remain abstinent (refrain from

heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per

year during the treatment period and for at least 5 months after the last dose of

atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last

TACE procedure.

- A woman is considered to be of childbearing potential if she is postmenarcheal,

has not reached a postmenopausal state (≥12 continuous months of amenorrhea with

no identified cause other than menopause), and has not undergone surgical

sterilization (removal of ovaries and/or uterus).

- Examples of contraceptive methods with a failure rate of < 1% per year include

bilateral tubal ligation, male sterilization, hormonal contraceptives that

inhibit ovulation, hormone-releasing intrauterine devices, and copper

intrauterine devices.

- The reliability of sexual abstinence should be evaluated in relation to the

duration of the clinical trial and the preferred and usual lifestyle of the

patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or

postovulation methods) and withdrawal are not acceptable methods of

contraception.

20. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use

contraceptive measures, and agreement to refrain from donating sperm, as defined

below:

- With female partners of childbearing potential, men must remain abstinent or use

a condom plus an additional contraceptive method that together result in a

failure rate of < 1% per year during the treatment period and for 6 months after

the last dose of bevacizumab or 1 month after the last TACE procedure. Men must

refrain from donating sperm during this same period.

- With pregnant female partners, men must remain abstinent or use a condom during

the treatment period and for 6 months after the last dose of bevacizumab or 1

month after the last TACE procedure to avoid exposing the embryo.

- The reliability of sexual abstinence should be evaluated in relation to the

duration of the clinical trial and the preferred and usual lifestyle of the

patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or

postovulation methods) and withdrawal are not acceptable methods of

contraception.

Exclusion Criteria:

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

2. Disease still amenable to curative surgery or transplantation or curative ablation.

3. Previous treatment with atezolizumab or bevacizumab.

4. Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1),

or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of

cancer immunotherapy for HCC.

5. Previous TACE or any other transarterial treatment for HCC

- Previous RFA / MWA allowed (refer to inclusion criterion #6)

- Other local therapies are prohibited (e.g. cryoablation, high-intensity focused

ultrasound, irreversible electroporation)

6. Extent of disease too advanced:

- Evidence of macrovascular invasion (even segmental) on baseline / eligibility

imaging

- Massive multinodular pattern preventing adequate TACE

- Extrahepatic disease

7. Tumor of diffuse infiltrative HCC type (hypovascular infiltrative tumors with

ill-defined borders)

8. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic

intervention (e.g. paracentesis) to maintain symptomatic control, within 6 months

prior to the first scheduled dose.

• Patients with ascites requiring pharmacologic intervention (e.g. diuretics) and

stable for ≥2 months on low doses of diuretics (spironolactone 100 mg/d or equivalent)

for ascites are eligible. Of note, diuretics for other indications such as congestive

heart failure are not considered in this regard.

9. Previous radiotherapy for HCC

10. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days 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.

11. Significant cardiovascular disease, such as cardiac disease (New York Heart

Association Class II or greater), myocardial infarction or cerebrovascular accident

within 3 months prior to randomization, as well as unstable arrhythmias (note: beta

blockers or digoxin are permitted), unstable angina, new-onset angina (begun within

the last 3 months).

12. Uncontrolled hypertension defined by a systolic blood pressure (BP) ≥150 mmHg or

diastolic blood pressure (BP) ≥100 mmHg, with or without antihypertensive medication.

Patients with initial blood pressure (BP) elevations are eligible if initiation or

adjustment of antihypertensive medication lowers pressure to meet entry criteria.

13. Current or recent (within 10 days prior to study treatment start) use of full-dose

oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed

to prophylactic) purpose.

14. History of or current pheochromocytoma.

15. Arterial or venous thrombotic or embolic events such as cerebrovascular accident

(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism ≤6

months prior to randomization.

16. With regards to eligibility for adequate TACE, patients presenting with either of the

following conditions are excluded:

- Past history of bilioenteric anastomosis or biliary procedure (e.g., endoscopic

papillotomy or biliary stenting) or patients with aerobilia

- Central biliary obstruction (right or left intrahepatic duct, common hepatic

duct, common bile duct)

- Celiac occlusion

17. Ongoing infection > grade 2 NCI-CTCAE version 5.0.

18. Patients with seizure disorder requiring medication.

19. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.

20. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event >CTCAE

grade 3 within 4 weeks prior to randomization.

21. Non-healing wound, ulcer, or bone fracture.

22. Renal failure requiring hemo- or peritoneal dialysis.

23. Substance abuse, medical, psychological or social conditions that may interfere with

the patient's participation in the study or evaluation of the study results.

24. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in

the formulation including a history of severe allergic, anaphylactic, or other

hypersensitivity reactions to chimeric or humanized antibodies or fusion protein;

known hypersensitivity to Chinese hamster ovary cell products or to any component of

the atezolizumab or bevacizumab formulation.

25. Positive test for human immunodeficiency virus (HIV)

26. Active tuberculosis

27. Interstitial lung disease with ongoing signs and symptoms at the time of informed

consent.

28. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced

pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis

obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on

screening chest computed tomography (CT) scan Note: History of radiation pneumonitis

within the radiation field (fibrosis) is permitted.

29. Persistent proteinuria of CTC Grade 3 or higher (> 3.5 g/24 hrs, measured by urine

protein: creatinine ratio on a random urine sample).

30. Any malabsorption conditions.

31. Pregnant or nursing women

32. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment

of the investigator, would make the patient inappropriate for entry into this study or

interfere significantly with the proper assessment of safety and toxicity of the

prescribed regimens.

33. Active or history of autoimmune disease including, but not limited to, myasthenia

gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid

arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's

granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis,

vasculitis, or glomerulonephritis.

Note: History of autoimmune-mediated hypothyroidism on a stable dose of thyroid

replacement hormone, or controlled Type 1 diabetes mellitus on a stable insulin

regimen may be eligible based on consultation with the sponsor's medical monitor.

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

- 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

previous 12 months

34. Pleural effusion or (thoracal/abdominal) ascites causing respiratory compromise

(≥CTCAE version 4.0 Grade 2 dyspnea).

35. Treatment with systemic immunosuppressive medication (including, but not limited to,

corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and

anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, 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 for the study.

- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids

for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose

corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible

for the study.

36. Use of any herbal remedies known to interfere with the liver or other major organ

functions. Patients must notify the investigator of all herbal remedies used during

the study.

37. Administration of a live, attenuated vaccine within four weeks prior to start of

enrollment, or anticipation that such a live attenuated vaccine will be required

during the study or within 5 months after the last dose of atezolizumab.

38. History of malignancy other than HCC within 3 years prior to screening, with the

exception of malignancies with a negligible risk of metastasis or death (e.g. 5-year

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

39. Receipt of an investigational drug within 28 days prior to initiation of study drug

40. Patient with any significant history of non-compliance to medical regimens or with

inability to grant reliable informed consent.

Studien-Rationale

Primary outcome:

1. Time to failure of treatment strategy (Time Frame - 48 months - assessed every 8 weeks (±7days)):
The primary endpoint is defined as the time from randomization until death or need for a further therapeutic option, defined for each arm as follows: Arm A: Time from randomization until the failure of strategy does not allow for further treatment with atezolizumab + bevacizumab; or death, whichever comes first. Arm B: Time from randomization until the failure of strategy does not allow for further TACE therapy; or death, whichever comes first. Failure of strategy (in brief): failure of strategy is reached in case of progressive disease accompanied by any of the following: loss of clinical benefit, unacceptable toxicity, liver function deterioration, therapy not further applicable for other reasons.



Secondary outcome:

1. Overall survival (OS) (Time Frame - 48 months):
Time from the date of randomization until the date of death due to any cause. A subject who has not died will be censored at last known date alive.

2. Overall Survival Rate at 24 months (OS@24) (Time Frame - 24 months):
The proportion of patients assigned to a treatment arm known to be alive at 24 months after randomization.

3. Objective Response Rate (ORR) (Time Frame - 48 months):
The proportion of patients assigned to a treatment arm with a confirmed best response of Complete Response (CR) or Partial Response (PR). Response will be assessed according to HCC mRECIST.

4. Time to Progression (TTP) (Time Frame - 48 months):
Time from the date of randomization until the date of first objective disease progression. Subjects who have not progressed will be censored at the last evaluable tumor assessment date prior to subsequent anti-cancer therapy. Subjects who die without experiencing a progress first will be censored on their date of death.

5. Time to loss of systemic treatment options (TTSYS) (Time Frame - 24 months):
Time from the date of randomization until the date the patient reaches a state of being unfit for any subsequent systemic treatment option (BSC as only option left) or the date of death whichever occurs first. Subjects who end systemic treatment at their own request will be censored at the day of end of systemic treatment. Subjects who are lost to follow-up will be censored at the date last known to be systemically treated.

6. Progression free survival (PFS) (Time Frame - 48 months):
Time from the date of randomization until the date of first objective disease progression or death. Subjects who did not progress or die will be censored at the last evaluable tumor assessment date prior to subsequent anti-cancer therapy.

7. Duration of Treatment (Time Frame - 24 months):
From start of treatment to permanent discontinuation of the treatment arms A and B.

8. Duration of Response (DOR) (Time Frame - 48 months):
Time from initial response to progressive disease or death in patients in treatment arms A and B with a confirmed best response of Complete Response (CR) or Partial Response (PR) according to HCC mRECIST. Subjects who did not progress or die will be censored at the last evaluable tumor assessment date prior to subsequent anti-cancer therapy.

9. Time to deterioration of liver function (Time Frame - 48 months):
Time from the date of randomization until liver function deterioration is registered according to definition given for failure of strategy. Only patients experiencing a deterioration of liver function are included into this analysis

10. Treatment-related and -unrelated toxicities (AEs, SAEs) according to NCI CTCAE v5.0 (Time Frame - 48 months):
Summary of adverse events by treatment arm and CTCAE (version 5.0) grade and frequency of clinically significant abnormal laboratory parameters.

11. QoL (EORTC QLQ-C30 and HCC18 sub-questionnaire) (Time Frame - 48 months):
QoL mean values and response as well as time to symptom deterioration (TTSD) defined as the time interval between randomization and the first decrease by ≥ 10-points. All randomly assigned patients with a baseline and at least one post-baseline assessment will be included in TTSD analyses. Patients without observed deterioration will be censored at the time of their last QoL assessment.

Studien-Arme

  • Experimental: Systemic therapy with atezolizumab + bevacizumab
    Patients receive atezolizumab 1200 mg flat dose plus bevacizumab 15 mg/kg given intravenously every 3 weeks until failure of strategy, participant request, or withdrawal of consent for a maximum of up to 24 months. The discontinuation of one of the study drugs for toxicity reasons does not qualify as failure of treatment strategy as long as the other drug can be continued according to protocol.
  • Active Comparator: Locoregional therapy with TACE
    Patients will receive initial TACE and - if required to achieve or improve an objective response - a second TACE after 8 weeks (±7 days window). Thereafter, additional TACE can be applied on demand until failure of strategy, participant request, or withdrawal of consent for a maximum of up to 24 months. TACE must be discontinued in cases of technical difficulties making additional TACE impossible. Only conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE) approaches are accepted as TACE therapy. However, consistency in the TACE procedure and the use of the chemotherapeutic agent has to be maintained for each individual patient.

Geprüfte Regime

  • Atezolizumab (Tecentriq):
    1200 mg atezolizumab intravenously Q3W (max 32 cycles, up to 24 months)
  • Bevacizumab (Avastin):
    15 mg/kg intravenously Q3W (max 32 cycles, up to 24 months)
  • TACE (transarterial chemoembolization):
    Locoregional therapy will be performed as a standard-of-care procedure

Quelle: ClinicalTrials.gov


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