Clinical Trials /

Atezolizumab Combined With Intratumoral G100 AnD Immunogenic Radiotherapy in Patients With Advanced Solid Tumors

NCT03915678

Description:

Basket trial concept to independently and simultaneously assess the effects of the association of atezolizumab + G100 + radiotherapy in multiple solid tumors.

Related Conditions:
  • Bladder Carcinoma
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Pancreatic Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab Combined With Intratumoral G100 AnD Immunogenic Radiotherapy in Patients With Advanced Solid Tumors
  • Official Title: Atezolizumab Combined With Intratumoral G100 AnD Immunogenic Radiotherapy in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: IB 2019-01
  • SECONDARY ID: 2019-000850-78
  • NCT ID: NCT03915678

Conditions

  • Solid Tumor, Adult
  • Pancreatic Cancer
  • Virus-associated Tumors
  • Non Small Cell Lung Cancer
  • Melanoma
  • Bladder Cancer
  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
Association atezolizumab + G100 + RTPopulation 1: Pancreatic cancer
Association atezolizumab + G100 + RTPopulation 2: Virus-associated tumors
Association atezolizumab + G100 + RTPopulation 3: Non-small lung cancer
Association atezolizumab + G100 + RTPopulation 4: Melanoma
Association atezolizumab + G100 + RTPopulation 5: Bladder cancer
Association atezolizumab + G100 + RTPopulation 6: Triple negative breast cancer

Purpose

Basket trial concept to independently and simultaneously assess the effects of the association of atezolizumab + G100 + radiotherapy in multiple solid tumors.

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 + G100 +
      radiotherapy, separately, in distinct populations of solid tumors:

        -  Population 1: pancreatic cancer

        -  Population 2: virus-associated tumors

        -  Population 3: non-small lung cancer

        -  Population 4: melanoma cancer

        -  Population 5: bladder cancer

        -  Population 6: triple negative breast cancer
    

Trial Arms

NameTypeDescriptionInterventions
Population 1: Pancreatic cancerExperimentalParticipants with pancreatic cancer will be treated with Atezolizumab combined with intratumoral G100 and radiotherapy.
  • Association atezolizumab + G100 + RT
Population 2: Virus-associated tumorsExperimentalParticipants with virus-associated tumors will be treated with Atezolizumab combined with intratumoral G100 and radiotherapy.
  • Association atezolizumab + G100 + RT
Population 3: Non-small lung cancerExperimentalParticipants with non-small lung cancer will be treated with Atezolizumab combined with intratumoral G100 and radiotherapy.
  • Association atezolizumab + G100 + RT
Population 4: MelanomaExperimentalParticipants with melanoma will be treated with Atezolizumab combined with intratumoral G100 and radiotherapy.
  • Association atezolizumab + G100 + RT
Population 5: Bladder cancerExperimentalParticipants with bladder cancer will be treated with Atezolizumab combined with intratumoral G100 and radiotherapy.
  • Association atezolizumab + G100 + RT
Population 6: Triple negative breast cancerExperimentalParticipants with triple negative breast cancer will be treated with Atezolizumab combined with intratumoral G100 and radiotherapy.
  • Association atezolizumab + G100 + RT

Eligibility Criteria

        Inclusion Criteria:

          1. Histology: histologically confirmed pancreatic cancer (population 1), virus-associated
             tumors tumors (population 2), non-small lung cancer (population 3), melanoma
             (population 4), bladder cancer (population 5), triple negative breast cancer
             (population 6). For population 2, diagnosis must be confirmed by the RRePS Network as
             recommended by the French NCI,

          2. Metastatic disease with at least one injectable lesion. Note that lesion must be a
             lymph node, or cutaneous, subcutaneous, intramuscular, liver metastasis,

          3. Age ≥ 18 years,

          4. ECOG, Performance status ≤ 1,

          5. At least three lesions: one injectable lesion (G100), 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 (outside any previously irradiated field,
             except if progressive as per RECIST at inclusion). This lesion will not be treated by
             radiotherapy and G100. However, note that lesion(s) that will be treated by
             radiotherapy and G100 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. Adequate hematological, renal, metabolic and hepatic functions:

               1. Hemoglobin ≥ 9 g/dl (participants may have received prior red blood cell [RBC]
                  transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 G/l,
                  platelet count ≥ 100 G/l, white blood cell count ≥ 2.5 G/l (or within local
                  laboratory normal limits) and lymphocyte count ≥ 0.75 G/l

               2. Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate
                  aminotransferase (ASP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of
                  extensive skeletal involvement for AP exclusively and ≤ 5 x ULN in case of liver
                  metastasis for AST and ALT).

               3. Direct bilirubin ≤ 1.5 x ULN,

               4. Albumin ≥ 25g/l.

               5. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30
                  ml/min (according to Cockroft and Gault formula).

               6. INR ≤ 1.5 x ULN

               7. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT
                  or PTT is within therapeutic range of intended use of anticoagulants

               8. Serum calcium within normal laboratory ranges,

               9. Thyroid function within normal laboratory ranges (TSH, free T3, free T4)

         11. No prior or concurrent malignant disease diagnosed or treated in the last 2 years
             except for adequately treated in situ carcinoma of the cervix, basal or squamous skin
             cell carcinoma, or in situ transitional bladder cell carcinoma,

         12. At least three weeks since last chemotherapy, immunotherapy or any other
             pharmacological treatment and/or radiotherapy,

         13. 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
             (according to the National Cancer Institute Common Terminology Criteria for Adverse
             Event (NCI-CTCAE, version 5.0)),

         14. Women of childbearing potential must have a negative serum pregnancy test within 7
             days prior to inclusion. Note that serum pregnancy test must be repeated 72 hours
             prior to receiving the first dose of study medication,

         15. 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.
             Acceptable methods for contraception include intrauterine device (IUD), oral
             contraceptive, subdermal implant and double barrier. Subjects of childbearing
             potential are those who have not been surgically sterilized (e.g., vasectomy for males
             and hysterectomy for females) or have not been free from menses for ≥ 1 year.

         16. Voluntary signed and dated written informed consents prior to any specific study
             procedure,

         17. Participants with a social security in compliance with the French law.

        Exclusion Criteria:

          1. Previous treatment with atezolizumab or TLS agonist

          2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,

          3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal
             metastases,

          4. Women who are pregnant or breast feeding,

          5. Participation to a study involving a medical or therapeutic intervention in the last
             30 days,

          6. Previous enrolment in the present study,

          7. Participant unable to follow and comply with the study procedures because of any
             geographical, familial, social or psychological reasons,

          8. Known hypersensitivity to CHO cell products or to any involved study drug or of its
             formulation components,

          9. History of severe allergic anaphylactic reactions to chimeric, human or humanized
             antibodies, or fusion proteins,

         10. Treatment with systemic immunosuppressive medications including, but not limited,
             cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within
             2 weeks prior to inclusion. Participants who have received acute and/or low-dose
             systemic immunosuppressant medications (e.g. a one-time dose of dexamethasone for
             nausea or chronic use of ≤10 mg/day of prednisone or dose-equivalent corticosteroid)
             may be enrolled in the study after discussion and approval by the Sponsor.

         11. The use of inhaled corticosteroids and mineral corticoids is allowed.

         12. Major surgical procedure, open biopsy or significant traumatic injury within 28 days
             before inclusion,

         13. Any of the following cardiac criteria:

               -  Congestive heart failure ≥ New York Heart Association (NHYA) class 2,

               -  Unstable angina (angina symptoms at rest), new-onset angina (begun within the
                  last 3 months),

               -  Myocardial infarction less than 6 months before inclusion

               -  Uncontrolled cardiac arrhythmias,

               -  Known left ventricular ejection fraction (LVEF) <50%

         14. Individuals deprived of liberty or placed under legal guardianship,

         15. Prior organ transplantation, including allogeneic stem cell transplantation,

         16. Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis, cirrhosis, fatty liver and inherited liver disease, ,

         17. History of intra-abdominal inflammatory process within the last 12 months such as, but
             not limited to, diverticulitis, peptic ulcer disease or colitis.

         18. 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.

               -  Participants with a history of autoimmune-related hypothyroidism on a stable dose
                  of thyroid replacement hormone are eligible,

               -  Participants with controlled Type I diabetes mellitus on a stable insulin regimen
                  are eligible,

               -  Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  only dermatologic manifestations <10% of the skin (e.g, participants with
                  psoriatic arthritis would be excluded) are eligible.

         19. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan. History of radiation pneumonitis in the
             radiation field (fibrosis) is permitted.

         20. Poorly controlled Type II diabetes mellitus defined as a screening fasting plasma
             glucose ≥160 mg/dL (or 8.8 mmol/L).

         21. Severe infections within 2 weeks prior to inclusion, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia.

         22. Received therapeutic oral or IV antibiotics within 2 weeks prior to inclusion.
             Participants receiving prophylactic antibiotics (e.g, for prevention of a urinary
             tract infection or chronic obstructive pulmonary disease) are eligible.

         23. Participants with oral anticoagulation therapy of the potential of bleeding. For ASA
             and anti-platelet agents, we follow the recommendations for injection from consensus
             guidelines. Based on the consensus guidelines from the Cardiovascular and
             Interventional Radiology Society of Europe, if a patient is to have a superficial
             lymph node or subcutaneous mass injected, NSAIDs, aspirin, or clopidogrel may be used
             and do not have to be withheld. For procedures with moderate or significant risk of
             bleeding, long-acting agents such as aspirin or clopidogrel should be discussed with
             the Sponsor and may need to be discontinued before beginning G100 therapy. (Higher
             risk would include deeper lesions or those within organs or with the potential for
             bleeding without the possibility of simple compression to help stop the bleeding).

         24. 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 has been clinically stable for >2 weeks prior to inclusion.

         25. Administration of a live, attenuated vaccine within 4 weeks before the start of study
             medication or anticipation that such a live attenuated vaccine will be required during
             the study. Influenza vaccination should be given during influenza season only
             (approximatively October to March). Patients must not receive live, attenuated
             influenza vaccine within 4 weeks prior to the start of study medication or at any time
             during the study or within 5 months after the last dose of atezoluzumab.

         26. Has known active hepatitis B or hepatitis C,

         27. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known
             acquired immunodeficiency syndrome (AIDS),

         28. Has a known history of tuberculosis.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assessment of the antitumor activity of atezolizumab combined with G100 and radiotherapy (independently for each population).
Time Frame:Within 6 months of treatment onset
Safety Issue:
Description:Antitumor activity will be assessed in terms of objective response rate within 24 weeks of treatment onset and is defined as the proportion of patients with complete response (CR) or partial response (PR) observed within 24 weeks of treatment onset (while treated with the investigational product), based on RECIST 1.1 criteria.

Secondary Outcome Measures

Measure:6-month objective response (OR) independently for each population.
Time Frame:6 months
Safety Issue:
Description: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.
Measure:6-month Progression-free rate (PFR), independently for each population.
Time Frame:6 months
Safety Issue:
Description: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.
Measure:Best overall response, independently for each population.
Time Frame:Throughout the treatment period, an expected average of 6 months
Safety Issue:
Description: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).
Measure:1-year progression-free survival, independently for each population.
Time Frame:1 year
Safety Issue:
Description: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.
Measure:2-year progression-free survival, independently for each population.
Time Frame:2 years
Safety Issue:
Description: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.
Measure:1-year overall survival, independently for each population.
Time Frame:1 year
Safety Issue:
Description:Overall survival is defined as the delay between the start date of treatment and the date of death (of any cause).
Measure:2-year overall survival, independently for each population.
Time Frame:2 years
Safety Issue:
Description:Overall survival is defined as the delay between the start date of treatment and the date of death (of any cause).
Measure: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
Safety Issue:
Description:Toxicity graded using the Common Terminology Criteria for Adverse Events version 5.
Measure:Tumor immune cells levels
Time Frame:before treatment onset and cycle 3 day 1 (each cycle is 21 days)
Safety Issue:
Description:Levels of immune cells in tumor will be measured by immunohistochemistry.
Measure: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)
Safety Issue:
Description:Levels of cytokines in blood will be measured by ELISA.
Measure: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)
Safety Issue:
Description:Levels of lymphocytes in blood will be measured by flow cytometry.
Measure: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)
Safety Issue:
Description:Levels of kynurenine in blood will be measured by ELISA.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Institut Bergonié

Trial Keywords

  • Immunotherapy
  • Radiotherapy
  • Oncology
  • Metastatic

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