Anti-PD-L1 and SAbR for Ovarian Cancer
Condition: Recurrent Epithelial Cancer of Ovary; Primary Peritoneal Carcinoma; Fallopian Tube Cancer
MeSH terms: Fallopian Tube Neoplasms; Ovarian Neoplasms
Intervention: Avelumab
Intervention description: Avelumab* (MSB0010718C; anti-PD-L1 is a fully human anti-PD- L1 IgG1 antibody)
Intervention MeSH terms: Avelumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Programmed death-1 receptor ligand (PD-L1) the ligand for PD-1 is a key therapeutic target in
      the reactivation of the immune response against multiple cancers. Pharmacologic inhibitors of
      PD-1 have also demonstrated significant anti-tumor activity and are currently under active
      clinical exploration. avelumab (MSB0010718C; anti-PD-L1 is a fully human anti-PD-L1 igG1
      antibody that has shown promising efficacy and an acceptable safety profile in multiple tumor
      types.

      Radiation therapy (RT) is one of the mainstream treatments of cancer therapy along with
      surgery and chemotherapy, yet RT is the only treatment that does not leave the patients
      immunocompromised (unlike chemotherapy) and keeps the dying tumor / antigen depot within the
      host (unlike surgery), providing an opportunity for antigen presentation. Therefore, RT is a
      rational choice to combine with immunotherapy for cancer treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Female subjects aged ≥ 18 years.

          2. Performance ECOG status of 0-2

          3. Patient is able and willing to comply with protocol and study procedures for the
             duration of the study including undergoing treatment and scheduled visits and
             examinations including follow-up visits.

          4. Adequate Physiologic function:

               -  Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100
                  × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused)

               -  Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and
                  AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 x ULN (for subjects with
                  documented metastatic disease to the liver).

               -  Renal: Estimated creatinine clearance ≥ 30 mL/min according to the
                  Cockcroft-Gault formula (or local institutional standard method)

          5. Pregnancy and contraception:

             Pregnancy test: Negative serum or urine pregnancy test at screening for women of
             childbearing potential.

             Contraception: Women of child-bearing potential and their male partners must agree to
             use adequate contraception (hormonal or barrier method of birth control; abstinence)
             prior to study entry.,

          6. Histologic diagnosis of recurrent epithelial ovarian ,fallopian ,peritoneal cancer

          7. Patients with platinum sensitive ovarian cancer must have progressed through at least
             one platinum containing regimen for recurrent disease.

          8. Patients with platinum resistant ovarian cancer must have progressed through at least
             one prior chemotherapy regimen for recurrent ovarian cancer.

          9. Patients must have received at least one prior chemotherapy regimen and up to any
             number of prior systemic regimens including chemotherapy and molecular targeted
             therapy other than PD1/ PDL1/ PDL2 inhibitors.

         10. Metastatic disease of at least two Non-CNS sites (including the index lesion to be
             treated) measurable by RECIST criteria with at least one site outside of the radiation
             field and evaluable by RECIST criteria for evaluation of response.

         11. Ability to understand and the willingness to sign a written informed consent -

        Exclusion Criteria:

          1. IMMUNOSUPRESSANTS: "Current use of immunosuppressive medication, EXCEPT for the
             following: a. Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
             intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10
             mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity
             reactions (e.g., CT scan premedication)."

          2. AUTOIMMUNE DISEASE: "Active autoimmune disease that might deteriorate when receiving
             an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or
             hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are
             eligible."

          3. ORGAN TRANSPLANTATION: "Prior organ transplantation including allogenic stem-cell
             transplantation."

          4. HIV/AIDS: "Known history of testing positive for HIV or known acquired
             immunodeficiency syndrome."

          5. HEPATITIS: "Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening
             (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test
             positive)"

          6. VACCINATION: "Vaccination within 4 weeks of the first dose of avelumab and while on
             trials is prohibited except for administration of inactivated vaccines "

          7. HYPERSENSITIIVTY TO STUDY DRUG: "Known prior severe hypersensitivity to
             investigational product or any component in its formulations, including known severe
             hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)"

          8. CARDIOVASCULAR DISEASE: "Clinically significant (i.e., active) cardiovascular disease:
             cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial
             infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure
             (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia
             requiring medication."

          9. OTHER PERSISTING TOXICITIES: "Persisting toxicity related to prior therapy (NCI CTCAE
             v. 4.03 Grade > 2); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤
             2 not constituting a safety risk based on investigator's judgment are acceptable."

         10. Other severe acute or chronic medical conditions including colitis, inflammatory bowel
             disease, pneumonitis, pulmonary fibrosis ,Severe COPD requiring > 3 hospitalization in
             the past year Or psychiatric conditions including recent (within the past year) or
             active suicidal ideation or behavior; or laboratory abnormalities that may increase
             the risk associated with study participation or study treatment administration or may
             interfere with the interpretation of study results and, in the judgment of the
             investigator, would make the patient inappropriate for entry into this study.

         11. No concomitant therapy with any of the following: IL2, interferon, or other non-study
             immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; or other
             investigational therapies; all such therapies must have been discontinued >4weeks
             prior to registration.

         12. No active TB,

         13. Patients with other invasive malignancies, with the exception of non-melanoma skin
             cancer, who had (or have) any evidence of other cancer present within the last 5 years
             or whose previous cancer treatment contraindicates this protocol therapy.

         14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

         15. Patients must not be pregnant or nursing.

         16. No history of prior treatment with inhibitor of PD-1 or PD-L1 or PDL2.

         17. Major surgery within 2 weeks prior to registration or first dose of drug

         18. Subjects who have had radiation therapy within 2 weeks prior to first dose of drug

         19. Uncontrolled adrenal insufficiency or active chronic liver disease

         20. Any history of CNS metastases that is not adequately treated (surgery or radiation )
             >14 days prior to registration.

         21. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalent) or other immunosuppressive medications within 14 days prior to
             the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses
             up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the
             absence of active autoimmune disease.