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

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ClinicalTrials.gov Identifier: NCT04224636
Recruitment Status : Recruiting
First Posted : January 13, 2020
Last Update Posted : October 26, 2020
Sponsor:
Information provided by (Responsible Party):
Enrico De Toni, Ludwig-Maximilians - University of Munich

Tracking Information
First Submitted Date  ICMJE December 19, 2019
First Posted Date  ICMJE January 13, 2020
Last Update Posted Date October 26, 2020
Actual Study Start Date  ICMJE April 6, 2020
Estimated Primary Completion Date March 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2020)
24-months survival rate [ Time Frame: 24 months ]
Percentage of patients alive after 24 months since randomization
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2020)
  • Median overall survival (mOS) [ Time Frame: 24 months ]
    Defined as the time from treatment initiation until death
  • Progression-free survival (PFS) [ Time Frame: 24 months ]
    Progression is defined according RECIST 1.1 and mRECIST
  • Overall response rate (ORR) [ Time Frame: 24 months ]
    Response is defined by RECIST 1.1 and mRECIST
  • Complete response rate (CRR) [ Time Frame: 24 months ]
    Defined by the percentage of patients with disappearance of tumor manifestation at radiological evaluation
  • Disease control rate (DCR) [ Time Frame: 24 months ]
    Defined as the percentage of patients who have achieved complete response, partial response and stable disease
  • Time to deterioration of liver function [ Time Frame: 24 months ]
    Defined as time from randomization to worsening of CTCAE grade for any of these parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, and international normalized ratio (INR)
  • Time to untreatable progression [ Time Frame: 24 months ]
    defined as time from randomization to progression not amenable to local treatment as per protocol, occurrence of vascular invasion or of extrahepatic spread, worsening of liver function to Child-Pugh score 8 or higher
  • Time to stage-progression [ Time Frame: 24 months ]
    Defined as time from randomization to disease progression to BCLC C stage
  • Time to first TACE (arm A) [ Time Frame: 24 months ]
    Defined as time from randomization to disease to the first TACE
  • Quality of life (QOL) [ Time Frame: 24 months ]
    Standardized assessment will be performed by using EORTC QLQ-C30 - European Organisation for Research and Treatment of Cancer - Quality of Life Core Questionnaire 30 items
  • Quality of life (QOL) [ Time Frame: 24 months ]
    Standardized assessment will be performed by using EORTC QLQ-HCC18 - European Organisation for Research and Treatment of Cancer - Quality of Life Core Questionnaire - Hepatocellular carcinoma module 18
  • Adverse Events [ Time Frame: 24 months ]
    Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Atezolizumab/Bevacizumab Followed by On-demand TACE or Initial Synchronous Treatment With TACE and Atezolizumab/Bevacizumab
Official Title  ICMJE 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 24-months Survival Rate in the Treatment of Unresectable Hepatocellular Carcinoma Patients
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatocellular Carcinoma Non-resectable
Intervention  ICMJE Combination Product: Atezolizumab Injection, Bevacizumab Injection
Atezolizumab and Bevacizumab will be administered prior to or in combination with TACE
Other Name: Chemoembolisation (TACE)
Study Arms  ICMJE
  • Experimental: Up-front Atezo/Bev, then TACE
    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
    Intervention: Combination Product: Atezolizumab Injection, Bevacizumab Injection
  • Experimental: Atezo/Bev combined with TACE
    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.
    Intervention: Combination Product: Atezolizumab Injection, Bevacizumab Injection
Publications * De Toni EN. Immune checkpoint inhibitors: use them early, combined and instead of TACE? Gut. 2020 Oct;69(10):1887-1888. doi: 10.1136/gutjnl-2019-319658. Epub 2019 Oct 14.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 9, 2020)
106
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2025
Estimated Primary Completion Date March 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Najib Ben Khaled, MD +49 89 4400 78160 najib.benkhaled@med.uni-muenchen.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04224636
Other Study ID Numbers  ICMJE AIO-HEP-0418
2019-002430-36 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Enrico De Toni, Ludwig-Maximilians - University of Munich
Study Sponsor  ICMJE Ludwig-Maximilians - University of Munich
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Ludwig-Maximilians - University of Munich
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP