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Atezolizumab/Bevacizumab Followed by On-demand TACE or Initial Synchronous Treatment With TACE and Atezolizumab/Bevacizumab (DEMAND)

L

Ludwig Maximilian University of Munich

Status and phase

Enrolling
Phase 2

Conditions

Hepatocellular Carcinoma Non-resectable

Treatments

Combination Product: Atezolizumab Injection, Bevacizumab Injection

Study type

Interventional

Funder types

Other

Identifiers

NCT04224636
2019-002430-36 (EudraCT Number)
AIO-HEP-0418

Details and patient eligibility

About

Aim of the study is 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.

Enrollment

106 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria

  1. Patient's signed informed consent
  2. Age ≥18 years at time of signing Informed Consent Form
  3. Ability to comply with the study protocol, according to investigator's judgement
  4. Life expectancy of at least 12 weeks
  5. HCC with histologically confirmed diagnosis
  6. Disease that is not amenable to curative surgical and/or local ablation but eligible for TACE
  7. ECOG Performance Status of 0 or 1
  8. Child-Pugh class A or B7
  9. Adequate hematologic and end-organ function
  10. Negative HIV test at screening

Key Exclusion Criteria

  1. Diffuse HCC or presence of vascular invasion or extrahepatic spread or more than 7 lesions or at least one lesion >= 7 cm

  2. Clinically relevant ascites

  3. Uncontrolled pleural effusion or pericardial effusion

  4. History or presence of hepatic encephalopathy

  5. Co-infection of HBV and HCV

  6. Patients on a liver transplantation list.

  7. Prior systemic therapy for HCC

  8. Prior treatment with TACE or selective internal radiation treatment (SIRT)

  9. Any condition representing a contraindication to TACE

  10. Major gastrointestinal bleeding within 4 weeks prior to randomization, untreated or incompletely treated varices with bleeding or high-risk for bleeding.

  11. Active or history of autoimmune disease or immune deficiency

  12. Prior allogeneic stem cell or solid organ transplantation

  13. 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

  14. Active tuberculosis

  15. Severe infection requiring antibiotics within 4 weeks prior to randomization

  16. Significant cardiovascular disease

  17. History of congenital long QT syndrome or corrected QT interval >500 ms at screening ECG

  18. Inadequately controlled arterial hypertension or prior history of hypertensive crisis or hypertensive encephalopathy

  19. Significant vascular disease including aortic aneurysm requiring surgical repair or peripheral arterial thrombosis with 6 months prior to randomization

  20. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization.

  21. 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

  22. History of intra-abdominal inflammatory process within 6 months prior to randomization, including but not limited to peptic ulcer disease, diverticulitis, or colitis

  23. Evidence of bleeding diathesis or significant coagulopathy

  24. 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.

  25. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at enrollment.

  26. Severe, non healing or dehisced wound, active ulcer, or untreated bone fracture

  27. History of malignancy other than HCC, with the exception of patients who have been disease-free for at least five years before enrollment or patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer

  28. Current or recent (within 10 days of randomization) use of acetylsalicyclic acid or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol

  29. Current or recent (within 10 days prior to randomization) use of full dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose.

  30. 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.

  31. 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

  32. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and antiPD-L1 therapeutic antibodies

  33. 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

  34. 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

  35. Treatment with systemic immunosuppressive medication 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 for adrenalcortical insufficiency are allowed.

  36. Major surgical procedure other than for diagnosis, open biopsy, or significant traumatic injury within 28 days prior to randomization, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 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

  37. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab

  38. Pregnant or breastfeeding females

  39. 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.

  40. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities

  41. Patient possibly dependent from the investigator including the spouse, children and close relatives of any investigator

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

106 participants in 2 patient groups

Up-front Atezo/Bev, then TACE
Experimental group
Description:
Patients will receive atezolizumab and bevacizumab iv every three weeks for up to 24 months. Upon detection of at least one unequivocal progressive hepatic lesion, selective TACE directed against progressive lesion(s) (sdTACE) will be performed. RFA or MWA are permitted as alternative to TACE to treat one or more lesion that cannot be reasonably selectively targeted by TACE
Treatment:
Combination Product: Atezolizumab Injection, Bevacizumab Injection
Atezo/Bev combined with TACE
Experimental group
Description:
First TACE will be performed as selectively as possible against all viable tumor lesions. Atezo/Bev will be initiated within three days from TACE. Upon detection of at least one unequivocal progressive hepatic lesion, treatment with Atezo/Bev will be continued if RFA or MWA can be used to treat this/these progressive lesion.
Treatment:
Combination Product: Atezolizumab Injection, Bevacizumab Injection

Trial contacts and locations

7

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Central trial contact

Enrico De Toni, MD

Data sourced from clinicaltrials.gov

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