A Trial of Durvalumab and Tremelimumab in Combination With SBRT in Patients With Metastatic Cancer

Inclusion Criteria

• •I1. Male or Female patients ≥18 years of age or older.
• •I2. Histologically or cytologically proven metastatic squamous cell carcinoma (from head and neck, oesophagus, lung, cervix, vagina, vulva or anus) with the following features:
• •Previously treated with at least one prior regimen (chemotherapy, signal transduction inhibitors or radiotherapy)
• •To be treated with radiotherapy at primary tumor site or metastatic site or menacing metastatic site.
• •The sites of metastases allowed are: soft tissue, peripheral lung, and liver.
• •Patients with brain and bone metastasis to be treated with radiotherapy are not allowed. Patients with asymptomatic brain metastasis can be included.
• •The total tumor volume to be irradiated must not exceed 400 cc.
• •I3. At least one tumor lesion must be accessible to radiation therapy and at least another tumor site can be spared from radiation therapy (unirradiated site).
• •I4. At least one unirradiated and one irradiated tumor site must be accessible to tumor biopsy.
• •I5. Known availability of an archived block
• •I6. The irradiated and unirradiated tumor sites must be measurable as per RECIST 1.1
• •I7. Patients must have no history of previous radiation therapy within the body area to be irradiated.
• •I8. Minimal wash-out periods from previous treatments to C1D1 must be
• •Any investigational agent \> 4 weeks
• •Bevacizumab \> 6 weeks
• •Chemotherapy \> 4 weeks
• •TKI \> 4 weeks
• •RANK ligand agonists \> 6 weeks
• •Immunosuppressive medication \> 28 days, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceeding 10 mg/day of prednisone, or an equivalent corticosteroid
• •Live attenuated vaccination \> 30 days
• •I9. WHO 0-1, Performance Status ECOG of 0-1
• •I10. Patients must have adequate organ function defined as follows:
• •Absolute neutrophil count of ≥ 1500/mm3,
• •Platelet count≥ 100,000/mm3,
• •Hemoglobin \> 9 g/dL,
• •Bilirubin ≤ 1.5 times the institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
• •Serum ALT and AST ≤2.5 ULN (or if liver metastases are present must be ≤ 5x ULN)
• •Serum creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (see formula in section 4.1).
• •I11. Patients must be free of significant comorbid conditions that would preclude safe administration or completion of protocol therapy.
• •I12. Female patients must either be of non-reproductive potential (ie, postmenopausal ≥ 12 months with no menses without an alternative medical cause OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry (within 72 hours before study drug start).
• •I13. Fertile men with a female partner of childbearing potential must agree to use male condom plus spermicide and childbearing potential women must have agreed to use at least one highly effective contraceptive method during treatment on this trial and for up to 180 days after the last of dose of Durvalumab + Tremelimumab or 90 days after the last dose of Durvalumab monotherapy, whichever is the longer period.
• •I14. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
• •I15. Patients must be affiliated to a social security system or beneficiary of the same.
• •E8. Current or planned use of forbidden concomitant medications :
• •Any investigational anticancer therapy not specified in this protocol
• •Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
• •Immunosuppressive medications including, but not limited to systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the management of investigational product-related AEs or in subjects with contrast allergies is acceptable. In addition, use of topical, inhaled and intranasal corticosteroids is permitted.
• •Live attenuated vaccines within 90 days of Durvalumab dosing or within 180 days of Durvalumab and Tremelimumab dosing. Inactivated vaccines, such as the injectable influenza vaccine, are authorized.
• •E9. Any prior Grade ≥ 3 irAE while receiving previous immunotherapy agent or any unresolved irAE \> Grade 1.
• •E10. Prior exposure to any anti-PD-1 or anti-PD-L1 or anti-CTLA4 antibody.
• •E11. Known allergy or hypersensitivity to humanized antibodies.
• •E12. Pregnant or breastfeeding women.
• •E13. Persons deprived of their freedom or under guardianship, or for whom it would be impossible to undergo the medical follow-up required by the trial, for geographic, social or psychological reasons.