Patient case: 32-year-old male with melanoma; genetic feature: NRAS (Q61H)

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

Summary: 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

Eligibility: 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.

Relevance to patient case: not relevant