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Atezolizumab Combined With BDB001 AnD Immunogenic Radiotherapy in Patients With Advanced Solid Tumors (AGADIR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03915678
Recruitment Status : Not yet recruiting
First Posted : April 16, 2019
Last Update Posted : September 30, 2020
Sponsor:
Collaborators:
Roche Pharma AG
National Cancer Institute, France
Seven and Eight Biopharmaceuticals Inc
Information provided by (Responsible Party):
Institut Bergonié

Brief Summary:
Basket trial concept to independently and simultaneously assess the effects of the association of atezolizumab + BDB001 + radiotherapy in multiple solid tumors.

Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Pancreatic Cancer Virus-associated Tumors Non Small Cell Lung Cancer Melanoma Bladder Cancer Triple Negative Breast Cancer Drug: Association atezolizumab + BDB001 + RT Drug: Association atezolizumab + BDB001+ RT Phase 2

Detailed Description:

6 independent, multicenter, prospective, single-arm phase II trials, based on 2-stage Simon's optimal design, will be conducted in parallel to assess the efficacy of atezolimab + BDB001+ radiotherapy, separately, in distinct populations of solid tumors:

  • Population 1: pancreatic cancer
  • Population 2: virus-associated tumors
  • Population 3: anti-PD-1/L1 refractory non-small lung cancer
  • Population 4: soft-tissue sarcoma
  • Population 5: anti-PD-1/L1 refractory bladder cancer
  • Population 6: anti-PD-1/L1 refractory triple negative breast cancer

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 247 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

6 independent single-arm, multicenter, phase II trials, based on 2-stage Simon's optimal design (Simon R, Controlled Clinical Trials 1989):

  • Population 1: pancreatic cancer
  • Population 2: virus-associated tumors
  • Population 3: non-small lung cancer
  • Population 4: soft-tissue sarcoma
  • Population 5: bladder cancer
  • Population 6: triple negative breast cancer
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Atezolizumab Combined With BDB001 AnD Immunogenic Radiotherapy in Patients With Advanced Solid Tumors
Estimated Study Start Date : January 2021
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : January 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Population 1: Pancreatic cancer
Participants with pancreatic cancer will be treated with Atezolizumab combined with BDB001 and radiotherapy.
Drug: Association atezolizumab + BDB001 + RT

A treatment cycle consits of 3 weeks. Atezolizumab will be administered as a 1-hour infusion on day 1 every 3 weeks (1200 mg).

BDB001 will be administered by a 30-minute intravenous infusion before atezolizumab, on Days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 BDB001 will be administered on Day 1 every 3 weeks.

Radiotherapy will start at least one week after the first administration of atezolizumab and at the latest before the 2nd administration. All participants will be treated by high dose irradiation in stereotactic conditions on non-injected metastasis: 3 to 5 fractions for a total dose between 27 Gy and 60 Gy.


Experimental: Population 2: Virus-associated tumors
Participants with virus-associated tumors will be treated with Atezolizumab combined with BDB001 and radiotherapy.
Drug: Association atezolizumab + BDB001+ RT

A treatment cycle consits of 3 weeks. Atezolizumab will be administered as a 1-hour infusion on day 1 every 3 weeks (1200 mg).

BDB001 will be administered by a 30-minute intravenous infusion before atezolizumab, on Days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 BDB001 will be administered on Day 1 every 3 weeks.

Radiotherapy will start at least one week after the first administration of atezolizumab and at the latest before the 2nd administration. All participants will be treated by high dose irradiation in stereotactic conditions on non-injected metastasis: 3 to 5 fractions for a total dose between 27 Gy and 60 Gy.


Experimental: Population 3: anti-PD-1/L1 refractory non-small lung cancer
Participants with anti-PD-1/L1 refractory non-small lung cancer will be treated with Atezolizumab combined with BDB001 and radiotherapy.
Drug: Association atezolizumab + BDB001+ RT

A treatment cycle consits of 3 weeks. Atezolizumab will be administered as a 1-hour infusion on day 1 every 3 weeks (1200 mg).

BDB001 will be administered by a 30-minute intravenous infusion before atezolizumab, on Days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 BDB001 will be administered on Day 1 every 3 weeks.

Radiotherapy will start at least one week after the first administration of atezolizumab and at the latest before the 2nd administration. All participants will be treated by high dose irradiation in stereotactic conditions on non-injected metastasis: 3 to 5 fractions for a total dose between 27 Gy and 60 Gy.


Experimental: Population 4: Soft-tissue sarcoma
Participants with soft-tissue sarcoma will be treated with Atezolizumab combined with BDB001 and radiotherapy.
Drug: Association atezolizumab + BDB001 + RT

A treatment cycle consits of 3 weeks. Atezolizumab will be administered as a 1-hour infusion on day 1 every 3 weeks (1200 mg).

BDB001 will be administered by a 30-minute intravenous infusion before atezolizumab, on Days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 BDB001 will be administered on Day 1 every 3 weeks.

Radiotherapy will start at least one week after the first administration of atezolizumab and at the latest before the 2nd administration. All participants will be treated by high dose irradiation in stereotactic conditions on non-injected metastasis: 3 to 5 fractions for a total dose between 27 Gy and 60 Gy.


Experimental: Population 5: anti-PD-1/L1 refractory bladder cancer
Participants with anti-PD-1/L1 refractory bladder cancer will be treated with Atezolizumab combined with BDB001 and radiotherapy.
Drug: Association atezolizumab + BDB001 + RT

A treatment cycle consits of 3 weeks. Atezolizumab will be administered as a 1-hour infusion on day 1 every 3 weeks (1200 mg).

BDB001 will be administered by a 30-minute intravenous infusion before atezolizumab, on Days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 BDB001 will be administered on Day 1 every 3 weeks.

Radiotherapy will start at least one week after the first administration of atezolizumab and at the latest before the 2nd administration. All participants will be treated by high dose irradiation in stereotactic conditions on non-injected metastasis: 3 to 5 fractions for a total dose between 27 Gy and 60 Gy.


Experimental: Population 6: Triple negative breast cancer
Participants with anti-PD-1/L1 refractory triple negative breast cancer will be treated with Atezolizumab combined with BDB001 and radiotherapy.
Drug: Association atezolizumab + BDB001 + RT

A treatment cycle consits of 3 weeks. Atezolizumab will be administered as a 1-hour infusion on day 1 every 3 weeks (1200 mg).

BDB001 will be administered by a 30-minute intravenous infusion before atezolizumab, on Days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 BDB001 will be administered on Day 1 every 3 weeks.

Radiotherapy will start at least one week after the first administration of atezolizumab and at the latest before the 2nd administration. All participants will be treated by high dose irradiation in stereotactic conditions on non-injected metastasis: 3 to 5 fractions for a total dose between 27 Gy and 60 Gy.





Primary Outcome Measures :
  1. Assessment of the antitumor activity of atezolizumab combined with BDB001 and radiotherapy in patients with pancreatic cancer. [ Time Frame: Within 6 months of treatment onset ]
    Antitumor activity will be assessed in terms of disease control rate within 24 weeks of treatment onset and is defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) observed within 24 weeks of treatment onset (while treated with the investigational product), based on RECIST 1.1 criteria.

  2. Assessment of the antitumor activity of atezolizumab combined with BDB001 and radiotherapy in patients with virus associated tumors. [ Time Frame: Within 6 months of treatment onset ]
    Antitumor activity will be assessed in terms of disease control rate within 24 weeks of treatment onset and is defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) observed within 24 weeks of treatment onset (while treated with the investigational product), based on RECIST 1.1 criteria.

  3. Assessment of the antitumor activity of atezolizumab combined with BDB001 and radiotherapy in patients with non-small cell lung cancer. [ Time Frame: Within 6 months of treatment onset ]
    Antitumor activity will be assessed in terms of disease control rate within 24 weeks of treatment onset and is defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) observed within 24 weeks of treatment onset (while treated with the investigational product), based on RECIST 1.1 criteria.

  4. Assessment of the antitumor activity of atezolizumab combined with BDB001 and radiotherapy in patients with soft-tissue sarcoma. [ Time Frame: 6 months of treatment onset ]
    Antitumor activity will be assessed in terms of 6-month progression-free rat (PFR) and is defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) observed at 6 months following treatment onset and more than 24 weeks, based on RECIST 1.1 criteria.

  5. Assessment of the antitumor activity of atezolizumab combined with BDB001 and radiotherapy in patients with bladder cancer. [ Time Frame: Within 6 months of treatment onset ]
    Antitumor activity will be assessed in terms of disease control rate within 24 weeks of treatment onset and is defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) observed within 24 weeks of treatment onset (while treated with the investigational product), based on RECIST 1.1 criteria.

  6. Assessment of the antitumor activity of atezolizumab combined with BDB001 and radiotherapy in patients with triple negative breast cancer. [ Time Frame: Within 6 months of treatment onset ]
    Antitumor activity will be assessed in terms of disease control rate within 24 weeks of treatment onset and is defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) observed within 24 weeks of treatment onset (while treated with the investigational product), based on RECIST 1.1 criteria.


Secondary Outcome Measures :
  1. 6-month Progression-free rate (PFR) in patients with pancreatic cancer. [ Time Frame: 6 months ]
    Progression-free rate is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST 1.1 criteria.

  2. 6-month Progression-free rate (PFR) in patients with virus-associated tumor. [ Time Frame: 6 months ]
    Progression-free rate is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST 1.1 criteria.

  3. 6-month Progression-free rate (PFR) in patients with non-small cell lung cancer. [ Time Frame: 6 months ]
    Progression-free rate is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST 1.1 criteria.

  4. 6-month Progression-free rate (PFR) in patients with bladder cancer. [ Time Frame: 6 months ]
    Progression-free rate is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST 1.1 criteria.

  5. 6-month Progression-free rate (PFR) in patients with triple negative breast cancer. [ Time Frame: 6 months ]
    Progression-free rate is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST 1.1 criteria.

  6. 6-month objective response rate (ORR) independently for each population. [ Time Frame: 6 months ]
    Objective response is defined as the proportion of patients with complete response (CR) or partial response (PR) observed at 6 months, based on RECIST 1.1 criteria.

  7. Objective response rate (ORR) within 24 weeks of treatment onset, independently for each population. [ Time Frame: Within 6 months ]
    Objective response is defined as the proportion of patients with complete response (CR) or partial response (PR) observed within 24 wekks after treatment onset, based on RECIST 1.1 criteria.

  8. Best overall response, independently for each population. [ Time Frame: Throughout the treatment period, an expected average of 6 months ]
    Best overall response is defined as the best response across all time points (RECIST 1.1). The best overall response is determined once all the data for the patient is known (RECIST 1.1).

  9. 1-year progression-free survival, independently for each population. [ Time Frame: 1 year ]
    Progression-free survival is defined as the delay between the start date of treatment and the date of progression (as per RECIST 1.1) or death (from any cause), whichever occurs first.

  10. 2-year progression-free survival, independently for each population. [ Time Frame: 2 years ]
    Progression-free survival is defined as the delay between the start date of treatment and the date of progression (as per RECIST 1.1) or death (from any cause), whichever occurs first.

  11. 1-year overall survival, independently for each population. [ Time Frame: 1 year ]
    Overall survival is defined as the delay between the start date of treatment and the date of death (of any cause).

  12. 2-year overall survival, independently for each population. [ Time Frame: 2 years ]
    Overall survival is defined as the delay between the start date of treatment and the date of death (of any cause).

  13. Safety profile, independently for each population: Common Terminology Criteria for Adverse Events version 5 [ Time Frame: Throughout the treatment period, an expected average of 6 months ]
    Toxicity graded using the Common Terminology Criteria for Adverse Events version 5.

  14. Tumor immune cells levels [ Time Frame: before treatment onset and cycle 3 day 1 (each cycle is 21 days) ]
    Levels of immune cells in tumor will be measured by immunohistochemistry.

  15. Blood cytokines levels [ Time Frame: baseline, cycle 1 day 1, cycle 2 day 1, cycle 3 day 1 and progression (each cycle is 21 days) ]
    Levels of cytokines in blood will be measured by ELISA.

  16. Blood lymphocytes levels [ Time Frame: baseline, cycle 1 day 1, cycle 2 day 1, cycle 3 day 1 and progression (each cycle is 21 days) ]
    Levels of lymphocytes in blood will be measured by flow cytometry.

  17. Blood kynurenine levels [ Time Frame: baseline, cycle 1 day 1, cycle 2 day 1, cycle 3 day 1 and progression (each cycle is 21 days) ]
    Levels of kynurenine in blood will be measured by ELISA.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. histologically confirmed pancreatic cancer, virus-associated tumors, non-small cell lung cancer, soft-tissue sarcomas, bladder cancer, triple negative breast cancer. For population 4, diagnosis must be confirmed by the RRePS Network as recommended by the French NCI,
  2. Metastatic disease,
  3. Age ≥ 18 years,
  4. ECOG ≤ 1,
  5. At least two lesions: one lesion that can be treated by radiotherapy and one site of disease that must be uni-dimensionally ≥ 10 mm considered as measurable according to RECIST v1.1. This lesion will not be treated by radiotherapy, however, note that lesion(s) that will be treated by radiotherapy will also be considered as measurable,
  6. Life expectancy > 6 months,
  7. At least one tumor site that can be biopsied for research purpose,
  8. Availability of archived paraffin-embedded tumor tissue for research purpose,
  9. Participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement,
  10. Participants who received prior anti-PD-1/L1 therapy must fulfill the following requirements

    • Have achieved a complete response, partial response or stable disease and subsequently had disease progression while still on anti-PD-1/L1 therapy
    • Have received at least two doses of an approved anti-PD-1/L1 therapy (by any regulatory authority)
    • Have demonstrated disease progression as defined by RECIST v1.1 within 18 weeks from the last dose of the anti- PD-1/L1 therapy.
  11. Adequate hematological, renal, metabolic and hepatic functions
  12. No prior or concurrent malignant disease needing an active treatment,
  13. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
  14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment, excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2,
  15. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to inclusion.
  16. Both women and men must agree to use an effective method of contraception throughout the treatment period and for five months after discontinuation of treatment.
  17. Voluntary signed and dated written informed consents prior to any specific study procedure,
  18. Participants with a social security in compliance with the French law.

Non-inclusion criteria:

  1. Previous treatment with a TLR agonist
  2. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases,
  3. Women who are pregnant or breast feeding,
  4. Participation in a study involving a medical or therapeutic intervention in the last 30 days,
  5. Known hypersensitivity to CHO cell products or to any involved study drug or of its formulation components,
  6. History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins,
  7. Treatment with systemic immunosuppressive medications including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within 2 weeks prior to inclusion.
  8. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before inclusion,
  9. Any of the following cardiac criteria: congestive heart failure ≥ New York Heart Association (NYHA) class 2, unstable angina, new-onset angina, myocardial infarction less than 6 months before inclusion, uncontrolled cardiac arrhythmias, known left ventricular ejection fraction (LVEF) <50%
  10. Individuals deprived of liberty or placed under legal guardianship,
  11. Prior organ transplantation, including allogeneic stem cell transplantation,
  12. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver and inherited liver disease,
  13. History of intra-abdominal inflammatory process within the last 12 months such as, but not limited to, diverticulitis, peptic ulcer disease or colitis.
  14. History of autoimmune disease including, but not limited to systemic lupus erythematosus (SLE), Sjögren's syndrome, glomerulonephritis, multiple sclerosis, rheumatoid arthritis, vasculitis, systemic immune activation, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Guillain-Barré syndrome, Bell's palsy.
  15. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
  16. Poorly controlled Type II diabetes mellitus defined as a screening fasting plasma glucose ≥160 mg/dL (or 8.8 mmol/L).
  17. Severe infections within 2 weeks prior to inclusion, including but not limited to SARS-Cov-2 infection, hospitalization for complications of infection, bacteremia, or severe pneumonia.
  18. Received therapeutic oral or IV antibiotics within 2 weeks prior to inclusion.
  19. Participant has spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease is clinically stable at least 14 days prior to inclusion.
  20. Administration of a live, attenuated vaccine within 4 weeks before the start of study medication .
  21. Has known active hepatitis B or hepatitis C,known history of Human Immunodeficiency or known acquired immunodeficiency syndrome, known history of tuberculosis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03915678


Contacts
Layout table for location contacts
Contact: Antoine ITALIANO, MD, PhD +33 5.56.33.33.33 a.italiano@bordeaux.unicancer.fr
Contact: Simone MATHOULIN-PELISSIER, MD, PhD s.mathoulin@bordeaux.unicancer.fr

Locations
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France
Institut Bergonié
Bordeaux, France, 33076
Contact: Antoine ITALIANO, MD, PhD       a.italiano@bordeaux.unicancer.fr   
Centre Georges François Leclerc
Dijon, France, 21079
Contact: Nicolas ISAMBERT, MD         
Principal Investigator: Nicolas ISAMBERT, MD         
Centre Oscar Lambret
Lille Cedex, France, 59020
Contact: Nicolas PENEL, MD, PhD         
Principal Investigator: Nicolas PENEL, MD, PhD         
Centre Léon Bérard
Lyon Cedex 08, France, 69373
Contact: Philippe CASSIER, MD         
Principal Investigator: Philippe CASSIER, MD         
Institut Paoli Calmettes
Marseille, France, 13273
Contact: Anthony GONCALVES, MD, PhD         
Principal Investigator: Anthony GONCALVES, MD, PhD         
Institut du Cancer de Montpellier
Montpellier, France, 34298
Contact: Diego TOSI, MD         
Principal Investigator: Diego TOSI, MD         
Institut Curie
Paris, France, 75005
Contact: Christophe LE TOURNEAU, MD         
Principal Investigator: Christophe LE TOURNEAU, MD         
Institut de Cancérologie de l'Ouest - Site René Gauducheau
Saint-Herblain, France, 44805
Contact: Steven LE GOUILLL, MD         
Principal Investigator: Steven LE GOUILLL, MD         
IUCT Oncopôle
Toulouse, France, 31052
Contact: Jean-Pierre DELORD, MD, PhD         
Principal Investigator: Jean-Pierre DELORD, MD, PhD         
Institut Gustave Roussy
Villejuif Cedex, France, 94805
Contact: Christophe MASSARD, MD, PhD         
Principal Investigator: Christophe MASSARD, MD, PhD         
Sponsors and Collaborators
Institut Bergonié
Roche Pharma AG
National Cancer Institute, France
Seven and Eight Biopharmaceuticals Inc
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Responsible Party: Institut Bergonié
ClinicalTrials.gov Identifier: NCT03915678    
Other Study ID Numbers: IB 2019-01
2019-000850-78 ( EudraCT Number )
First Posted: April 16, 2019    Key Record Dates
Last Update Posted: September 30, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut Bergonié:
Immunotherapy
Radiotherapy
Oncology
Metastatic
Additional relevant MeSH terms:
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Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Neoplasms
Breast Diseases
Skin Diseases
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs