RACIN in Patients With Advanced TIL-negative Solid Tumors
RACIN in Patients With Advanced TIL-negative Solid Tumors
Subjects with locally advanced or metastatic incurable Tumor Infiltrating Lymphocytes
 (TIL)-negative solid tumors who are not eligible for, declined or failed standard therapy
 will be treated with a combination nivolumab, low-dose ionizing radiation (RT) (0.5-2 Gy),
 aspirin (ASA)(cohorts 1 and 2)/celecoxib (cohorts 3, 4 and Phase Ib), and either ipilimumab
 or low-dose cyclophosphamide. The study comprises 2 phases: The aim of Phase Ia, is to
 determine safety and tolerability of a given combination therapy, as well as the maximum
 tolerated dose (MTD) or recommended phase Ib dose (RP1bD) of radiotherapy. Phase Ib aims to
 further explore safety and tolerability of this treatment in an expansion cohort.

 In Phase Ia, 4 distinct cohorts will receive the following combination therapy:

 Cohort1: combination therapy for 5 cycles (C0-C4) which includes: RT 0.5 Gy every 2 weeks
 (Q2W), Cy (200 mg/m2) Q2W (cycles C0 to C4); ASA (300 mg) daily, with nivolumab 240 mg flat
 dose Q2W and ipilimumab 1 mg/kg every 6 weeks (Q6W) will be administered (cycles C1 to C4).

 Cohort2: combination therapy for 5 cycles (C0-C4) which includes: RT 1 Gy every 2 weeks
 (Q2W), Cy (200 mg/m2) Q2W (cycles C0 to C4); ASA (300 mg) daily, with nivolumab 240 mg flat
 dose Q2W and ipilimumab 1 mg/kg (Q6W) will be administered (cycles C1 to C4).

 Cohorts 3a and 4a: Patients will receive Cy (200 mg/m2) Q2W, celecoxib (2x200mg daily),
 nivolumab (240 mg flat dose) Q2W, and low-dose radiation. Cohort 3a will receive 1 Gy of
 low-radiation dose and cohort 4a will receive 2 Gy.

 Cohorts 3b and 4b: Patients will receive nivolumab (240 mg flat dose) Q2W, ipilimumab 1 mg/kg
 (Q6W), celecoxib (2x200mg daily) and low-dose radiation. Cohort 3b will receive 1 Gy of
 low-radiation dose and cohort 4b will receive 2 Gy.

 In Phase Ia, the safety of combination (nivolumab, celecoxib, low-dose irradiation and
 cyclophosphamide) or (nivolumab, celecoxib, low-dose irradiation and ipilimumab) will be
 evaluated , and MTD or RP1bD will be defined. RP1bD will be the MTD or, in the absence of
 dose limiting toxicities (DLTs), the biologically best RT dose based on pharmacodynamics
 parameters.

 In Phase Ib, patients will be treated with the MTD or RP1bD dose of RT and will follow the
 selected schema of treatment used in the Phase Ia cohort 3 or 4. At the end of the 5th cycle,
 patients eligible for nivolumab maintenance, will be treated with nivolumab at 240 mg Q2W
 until progression or excessive toxicity; celecoxib will be maintained according to
 tolerability.
Pre-screening registration

 Inclusion Criteria:

 1. Signed pre-screening Informed Consent Form

 2. Patients with recurrent or metastatic solid tumor (any histology), who progress after
 at least one standard therapy for advanced disease

 3. Patient willingness and acceptance to participate in the immunology research is
 mandatory

 4. At least one lesion accessible to biopsy without putting patient at risk

 5. Biopsies obtained previously (within a maximum of 12 weeks before pre-screening
 visit), outside this protocol, for TIL assessment can be also considered for patient
 selection. Fresh tumor biopsies for subsequent translational studies will be used as
 baseline and collected at pre-screening (when biopsy will be performed for TIL status)
 or at screening (when archival biopsy will be used for TIL status). Biopsy from
 metastatic lymph nodes is accepted.

 6. Eastern Cooperative Oncology Group (ECOG) clinical performance status: 0-1 for all
 patients, independently of the number of previous lines of therapy.

 7. Life expectancy of ≥ 12 weeks

 8. Patients with Glycose-6-Phosphate Dehydrogenase (G6PD) deficiency or any other
 hereditary coagulation disorder are excluded, as well as patients with clinical
 history of Reye syndrome

 9. Adequate serology defined by the following laboratory results obtained during
 pre-screening period (day-28 to day-14).

 1. Seronegative for HIV infection (anti-HIV-1/-2)

 2. Seronegative for hepatitis B infection (HBs Ag, total anti-hemoglobin C (HBc),
 anti-HBs). Patients with past or resolved hepatitis B infection (defined as
 having a negative hepatitis B surface antigen HBsAg test and a positive anti-HBc
 antibody test) are eligible, if hepatitis B virus (HBV) DNA test is negative.

 3. Seronegative for hepatitis C infection (anti-HCV): if a patient has positive
 anti-HCV antibody, a negative hepatitis C virus (HCV) RNA need to be obtain to
 register the patient.

 Study registration

 Inclusion Criteria

 1. Signed main study Informed Consent Form

 2. Absence of tumor-infiltrating intraepithelial Cluster of differentiation-8 positive T
 cells (CD8+ T cells) by immunohistochemistry (IHC) on baseline biopsy defined as <5
 CD8+ cells per high power field of tumor

 3. At least one lesion accessible to biopsy without putting patient at risk

 4. Number of metastatic lesions viewed on Positron emission tomography-computed
 tomography (PET/CT) scan: for both Phase Ia and Phase Ib, the patient may have any
 number of metastatic lesions. A maximum of 10 metastatic lesions visible by PET/CT
 scan will be irradiated at the investigator's discretion. It is at the discretion of
 the investigator to exclude a metastatic site from the radiation field that, due to
 the radiotherapy volume, dose or location too close to a healthy organ, may put the
 patient at risk of suffering from radiation induced toxicity. If this would be the
 only metastatic site to be irradiated, the concerned patient will be excluded from the
 study.

 5. Absence of any psychological, familial, sociological or geographical condition
 potentially hampering compliance with the study protocol

 6. Adequate hematologic and end-organ function, defined by the following laboratory
 results obtained within 14 days prior to the first study treatment:

 1. Absolute neutrophil count ≥ 1.5 g/L (without granulocyte colony-stimulating
 factor support within 2 weeks prior registration)

 2. White Blood Cell (WBC) counts > 2.5 g/L and < 15 g/L

 3. Lymphocyte count ≥ 0.5 g/L

 4. Platelet count ≥ 100 g/L (without transfusion within 1 week prior registration)

 5. Hemoglobin ≥ 90 g/L (Patients may be transfused to meet this criterion but it
 should not be done within 1 week prior registration)

 6. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and
 alkaline phosphatase ≤ 2.5 x ULN (with the exception for patients with documented
 liver metastases: AST, ALT and alkaline phosphatase ≤ 5 x ULN)

 7. Serum bilirubin ≤ 1.5 x ULN (with the exception for: patients with known or
 suspicion of Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be
 enrolled)

 8. Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5
 X ULN unless subject is receiving anticoagulant therapy as long as PT or Partial
 Thromboplastin Time (PTT) is within therapeutic range of intended use of
 anticoagulants; Activated Partial Thromboplastin Time (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.

 9. Serum albumin > 25 g/L

 10. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥ 40 ml/min on the basis of
 Cockcroft-Gault Formula

 7. No prior radiation therapy in areas of desired radiation

 8. Patients may have had prior therapy provided a washout period of 4 weeks prior to
 registration is allowed. Exception: hormone therapy for breast and prostate cancer is
 allowed to be continued during the study.

 9. Recovery from any toxic effects of prior therapy before registration to ≤ Grade 1 per
 the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
 CTCAE v4.03) except for toxicities described below, as they do not put at risk the
 patient's condition and do not require systemic immunosuppressive steroids at any
 dose, including but not limited to: fatigue, alopecia, skin disorders, stable
 neuropathy, endocrinopathies requiring replacement treament.

 Note: for other medical conditions, or for any other toxicity with a higher grade but
 controlled by adequate treatment, prior discussion and agreement with the trial chair
 is mandatory.

 Note: Patients may have undergone surgical procedures within the past 3 weeks, as long
 as all toxicities have recovered to grade 1 or less.

 10. For women of childbearing potential (WOCBP: sexually mature women who have not
 undergone a hysterectomy, have not been naturally post-menopausal for at least 12
 consecutive months or have a serum follicle-stimulating hormone (FSH) < 40 Millions
 International Units (mIU)/ml):

 1. Agreement to use 2 acceptable methods of contraception during participation in
 the trial and for 6 months after last study combined treatment and after 5 months
 of maintenance treatment

 2. Women must have a negative urine pregnancy test within 7 days before
 registration. A positive urine test must be confirmed by a serum pregnancy test,
 or menopausal as per National Comprehensive Cancer Network (NCCN) guidelines.

 11. For men: agreement to use 2 acceptable methods of effective contraception during
 participation in the trial and for 7 months after last study treatment (combined or
 maintenance treatment). Female partners of men who take part in this trial must also
 use at least one method of effective contraception during the trial and 7 months after
 last study treatment (combined or maintenance).

 Exclusion Criteria:

 1. Patients with soft tissue sarcoma, glioblastoma, or lymphoma are excluded.

 2. Pregnant or breast-feeding women.

 3. Symptomatic brain or leptomeningeal disease; any brain metastases must be stable for
 at least 6 months

 4. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
 drainage procedures (once monthly or more frequently)

 5. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected
 serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of
 bisphosphonate therapy or denosumab

 a) Patients who are receiving bisphosphonate therapy or denosumab specifically to
 prevent skeletal events and who do not have a history of clinically significant
 hypercalcemia are eligible.

 6. Life expectancy of < 12 weeks

 7. Current, recent (within 4 weeks prior to registration), or planned participation in an
 experimental drug study

 8. New York Heart Association Class II or greater congestive heart failure

 9. History of myocardial infarction or unstable angina within 6 months prior registration

 10. History of stroke or transient ischemic attack within 6 months prior registration

 11. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
 recent peripheral arterial thrombosis) within 6 months prior registration)

 12. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
 therapeutic anticoagulation)

 13. Patients with active peptic or duodenal ulceration (within 4 weeks prior to
 registration)

 14. Current or recent (within 14 days prior registration) treatment use of dipyramidole,
 ticlopidine, clopidogrel, cilostazol, prasugrel, or ticagrelor

 15. Current or recent (within 14 days prior registration) use of full-dose oral or
 parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to
 prophylactic) purpose

 1. Prophylactic anticoagulation for the patency of venous access devices is allowed,
 provided the activity of the agent results in an International Normalized Ratio
 (INR) < 1.5 x ULN and aPTT is within normal limits within 2 weeks prior
 registration.

 2. Prophylactic use of low molecular-weight heparin (e.g., enoxaparin) is allowed.

 16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
 chimeric or humanized antibodies or fusion proteins or allergy to biopharmaceuticals
 produced in Chinese hamster ovary cells

 17. Known hypersensitivity to any component of the Investigational Medicinal Products
 (IMPs)

 18. History of autoimmune disease, including but not limited to myasthenia gravis,
 myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
 inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
 syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
 multiple sclerosis, vasculitis, or glomerulonephritis. The following exceptions are
 considered:

 1. Patients with a history of autoimmune-related hypothyroidism on a stable dose of
 thyroid replacement hormone are eligible for this study.

 2. Patients with controlled Type I diabetes mellitus on a stable insulin regimen are
 eligible

 19. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
 obliterans), druginduced pneumonitis, idiopathic pneumonitis, or evidence of active
 pneumonitis on screening chest Computerized Tomography (CT) scan. Exception: history
 of radiation pneumonitis in previous radiation field (fibrosis) is permitted provided
 that this area does not undergo current low dose irradiation as part of this protocol.

 20. Severe infections within 4 weeks prior registration including but not limited to
 hospitalization for complications of infection, bacteremia, or severe pneumonia

 21. Signs or symptoms of infection within 2 weeks prior registration

 22. Received therapeutic oral or IV antibiotics within 2 weeks prior registration.
 Exception: patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic
 obstructive pulmonary disease exacerbation or for dental extraction) are eligible.

 23. Prior allogeneic stem cell or solid organ transplant

 24. Administration of a live, attenuated vaccine within 4 weeks before registration.
 Exception: influenza vaccination should be given during influenza season only
 (approximately October to March). Patients must not receive live, attenuated influenza
 vaccine within 4 weeks prior registration or at any time during the study.

 25. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
 laboratory finding giving reasonable suspicion of a disease or condition that
 contraindicates the use of an investigational drug or that may affect the
 interpretation of the results or render the patient at high risk from treatment
 complications

 26. Patients who have received prior treatment with anti-Programmed Cell Death-1 (PD1),
 anti-Programmed Cell Death Ligand-1 (PD-L1) or anti-Cytotoxic T-lymphocyte Associated
 4 (CTLA-4) may be enrolled, provided at least 5 half-lives (approximately 75 days)
 have elapsed from the last dose to the registration and there was no history of severe
 immune-mediated adverse effects from such therapy (NCI CTCAE Grade 3 and 4).

 27. Treatment with systemic immunostimulatory agents (including but not limited to
 interferon-alpha (IFN-a), interleukin-2 (IL-2)) for any reason within 6 weeks or five
 half-lives of the drug, whichever is shorter, prior registration

 28. Treatment with systemic immunosuppressive medications (including but not limited to
 prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide,
 and anti-tumor necrosis factor (anti-TNF) agents) within 2 weeks prior registration

 1. Patients who have received acute, low-dose, systemic immunosuppressant
 medications (e.g., a one-time dose of dexamethasone for nausea) or physiologic
 replacement doses (i.e., prednisone 5-7.5 mg/day) for adrenal insufficiency may
 be enrolled in the study.

 2. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
 is allowed.