A randomized, 2-arm non-comparative phase II study on the efficacy of atezolizumab and Roche bevacizumab (Atezo/Bev) followed by on-demand selective TACE (sdTACE) upon detection of disease progression or of initial synchronous treatment with TACE and Atezo/Bev on objective response rate in the treatment of unresectable hepatocellular carcinoma patients (DEMAND)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Klinikum der Universitaet Muenchen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Apr 2020 → ongoing

Decision date (initial)

2024-10-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

ROCHE

External identifiers

EU CT number

2024-512682-14-00

EudraCT number

2019-002430-36

ClinicalTrials.gov

NCT04224636

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy of up-front atezolizumab/ bevacizumab (Atezo/Bev) followed by on-demand selective transarterial chemoembolization (sdTACE) and of initial synchronous treatment with TACE and Atezo/Bev in the treatment of unresectable HCC patients.

Secondary objectives 1

1. To evaluate the efficacy, safety and quality of life of treatment with Atezo/Bev in combination with TACE

Conditions and MedDRA coding

Non-resectable hepatocellular carcinoma (HCC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Patient’s signed informed consent
2. 2. Age ≥ 18 years at time of signing Informed Consent Form
3. 3. Ability to comply with the study protocol, according to investigator's judgement
4. 4. Life expectancy of at least 12 weeks
5. 5. HCC with histologically confirmed diagnosis. If no archival sample is available and the specific risk of performing the biopsy according to the investigator’s opinion is considered to outweigh the benefits of diagnostic confirmation, HCC can be diagnosed based on typical diagnostic imaging on dynamic CT or MRI according to AASLD criteria, after consultation with the sponsor.
6. 6. Disease that is not amenable to curative surgical and/or local ablation treatment according to consensus resolution of the multidisciplinary tumor board of the trial center but eligible for TACE, with tumor burden below 50% of liver volume.
7. 7. At least one measurable (per RECIST 1.1) untreated lesion
8. 8. ECOG Performance Status of 0 or 1
9. 9. Child-Pugh class A or B7
10. 10. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization, unless otherwise specified (deviations of individual laboratory values are permitted with the sponsor's consent if an integrated assessment of all findings does not suggest organ dysfunction that would be incompatible with the study): – ANC ≥1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support – Lymphocyte count ≥ 0.5 x 109/L (500/µL) – Platelet count ≥ 50 x109/L (50,000/µL) without transfusion – Hemoglobin ≥ 90 g/L (9 g/dL); patients may be transfused to meet this criterion. – AST, ALT, and alkaline phosphatase ≤ 5 x upper limit of normal (ULN) – Serum bilirubin ≤ 3 x ULN – Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula) – Serum albumin ≥ 28 g/L (2.8 g/dL) – For patients not receiving therapeutic anticoagulation: INR <1.5 Urine dipstick for proteinuria < 2+ (within 14 days prior to initiation of study treatment), unless a subsequent 24-hour urine collection demonstrates < 1 g of protein in 24 hours.
11. 11. Negative HIV test at screening
12. 12. Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test. For patients with active hepatitis B virus (HBV): HBV DNA < 500 IU/mL obtained within 28 days prior to randomization, and Anti-HBV treatment (per local standard of care) for a minimum of 14 days prior to randomization and willingness to continue treatment for the length of the study
13. 13. For females of childbearing potential (FCBP): negative pregnancy test within 14 days before randomization and 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 or 6 months after the last dose of bevacizumab. 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 partner’s 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.
14. 14. 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. 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 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 44

1. 1. Diffuse HCC or presence of vascular invasion or extrahepatic spread (including extrahepatic lymph node affection or metastasis) or more than 7 lesions or at least one lesion ≥ 7 cm
2. 2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
3. 3. Clinically significant ascites on screening, as defined by clinically detectable ascites on physical examination or by ascites with the need for paracentesis.
4. 4. Uncontrolled pleural effusion or pericardial effusion.
5. 5. History or presence of hepatic encephalopathy
6. 6. Co-infection of HBV and HCV Patients with a history of HCV infection but who are negative for HCV RNA by polymerase chain reaction (PCR) will be considered non-infected with HCV.
7. 7. Patients actively listed for transplantation or who are not yet listed for transplantation but are potentially eligible for transplantation by fulfilling the Milan criteria for liver transplantation as defined by the “Richtlinien der Bundesärztekammer gem. § 16 TPG zur Lebertransplantation” (7)
8. 8. Prior systemic therapy for HCC
9. 9. Prior treatment with TACE or selective internal radiation treatment (SIRT) within six months before randomization
10. 10. Patients who received prior local or locoregional treatment are eligible for the study provided that the target lesion(s) have not been previously treated or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST version 1.1
11. 11. Any condition representing a contraindication to TACE
12. 12. Major gastrointestinal bleeding within 4 weeks prior to randomization.
13. 13. Patients with untreated or incompletely treated varices with bleeding or high-risk for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months prior to randomization do not need to repeat the procedure. Those who have received banding and/or sclerotherapy and with no bleeding event within the prior 6 months are eligible provided that a re-endoscopy is performed and that varices remained obliterated, minimal or Grade I
14. 14. 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 (i.e., 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
15. 15. Prior allogeneic stem cell or solid organ transplantation
16. 16. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. If any of these lung diseases is suspected based on the patient’s history or the integrated evaluation of clinical and radiological records, an additional spirometry should be conducted.
17. 17. Active tuberculosis (as ruled out by clinical evaluation including medical history, physical examination, radiographic findings on baseline CT/ magnetic resonance imaging [MRI] of chest/abdomen/pelvis; if active tuberculosis is suspected, tuberculosis testing should be performed as per local standard of care).
18. 18. Severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia or any active infection (bacterial, viral or fungal) requiring systemic therapy within 4 weeks prior to randomization. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
19. 19. Significant cardiovascular disease such as New York Heart Association Class II or greater heart failure, myocardial infarction or cerebrovascular accident within 6 months prior to randomization, despite anti-arrhythmic therapy unstable cardiac arrhythmia > grade 2 NCI CTCAE, or unstable angina
20. 20. History of congenital long QT syndrome or corrected QT interval >500 ms at screening ECG or repeated demonstration of a corrected QT interval >450 ms
21. 21. Inadequately controlled arterial hypertension (defined as systolic blood pressure  150 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg) or prior history of hypertensive crisis or hypertensive encephalopathy.
22. 22. Significant vascular disease including aortic aneurysm requiring surgical repair or peripheral arterial thrombosis with 6 months prior to randomization
23. 23. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization.
24. 24. 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
25. 25. History of intra-abdominal inflammatory process within 6 months prior to randomization, including but not limited to peptic ulcer disease, diverticulitis, or colitis
26. 26. Evidence of bleeding diathesis or significant coagulopathy
27. 27. 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.
28. 28. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at enrollment.
29. 29. Severe, non healing or dehisced wound, active ulcer, or untreated bone fracture
30. 30. Prior or concomitant malignancy other than HCC unless it has been adequately treated or is considered not to affect the staging and prognosis of the patient.
31. 31. Current therapy with dual antiplatelet treatment
32. 32. Current use of full dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose. Prophylactic use of anticoagulation is allowed.
33. 33. Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed.
34. 34. Treatment with a live, attenuated vaccine within 4 weeks prior to randomization, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.
35. 35. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
36. 36. Hypersensitivity to atezolizumab or bevacizumab or any of the excipients, known hypersensitivity to Chinese hamster ovary cell products, known hypersensitivity to human or humanized antibodies
37. 37. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to randomization
38. 38. Treatment with systemic immunosuppressive medication (including, but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antiTNF- agents) within 2 weeks prior to randomization, 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. Inhaled corticosteroids for chronic obstructive pulmonary disease or bronchial asthma, supplemental mineralocorticosteroids or low-dose corticosteroids (e.g., up to prednisolone 10 mg/d or equivalent) are allowed.
39. 39. Major surgical procedure (as defined by the investigator) or significant traumatic injury within 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
40. 40. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab
41. 41. Pregnant or breastfeeding females
42. 42. Participation in a clinical trial or experimental drug treatment within 28 days prior to inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
43. 43. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
44. 44. Patient possibly dependent from the investigator including the spouse, children and close relatives of any investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To evaluate the efficacy of up-front atezolizumab/ bevacizumab (Atezo/Bev) followed by on-demand selective transarterial chemoembolization (sdTACE) and of initial synchronous treatment with TACE and Atezo/Bev in the treatment of unresectable HCC patients Corresponding primary endpoint: Objective response rate (according to RECIST v1.1) (as assessed by local investigator) (ORR)

Secondary endpoints 1

1. To evaluate the efficacy, safety and quality of life of treatment with Atezo/Bev in combination with TACE Corresponding secondary endpoints:• Overall survival (OS) • 24-months survival rate • Progression-free survival (PFS) • Complete response rate (CRR) • Disease control rate (DCR) • Time to deterioration of liver function, defined as time from randomization to worsening of CTCAE grade compared with baseline and persisting for ≥ 30 days for any of these parameters: aspartate aminotransferas

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Klinikum der Universitaet Muenchen AöR

Sponsor organisation

Klinikum der Universitaet Muenchen AöR

Address

Marchioninistrasse 15, Hadern Hadern

City

Munich

Postcode

81377

Country

Germany

Scientific contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

Sponsor Delegated Person

Public contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

Sponsor Delegated Person

Third parties 2

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications