A Phase II Trial of Avelumab in Patients With Recurrent or Progressive Osteosarcoma
Condition: Osteosarcoma
MeSH terms: Osteosarcoma
Intervention: Avelumab; Questionnaires
Intervention description: Patients will be administered avelumab at a dose of 10 mg/kg intravenously (IV) over 60 minutes on days 1 and 15 of each cycle, with a cycle lasting 28 days. Patients will receive avelumab every 2 weeks in cycles of 28 days for up to 24 months, or 26 cycles.; To assess quality of life, patients will complete questionnaires at four time points.
Intervention MeSH terms: Avelumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 12 Years
Maximum age: 49 Years
Healthy volunteers: No
Keywords: Osteosarcoma; PD-L1; Immunotherapy

Summary:

      This clinical trial seeks to determine if avelumab will be effective in facilitating removal
      of all gross tumor in the event of a relapse of osteosarcoma in pediatric patients. Avelumab
      will be evaluated using dosing that has previously been determined in adult studies.

      Primary Objectives:

        -  To estimate the response rate to 4 cycles of avelumab in patients with recurrent or
           progressive osteosarcoma.

        -  To estimate the 16-week progression free survival of patients with recurrent or
           progressive osteosarcoma after treatment with avelumab.

      Secondary Objective:

        -  To describe the toxicities associated with the administration of avelumab in patients
           with recurrent or progressive osteosarcoma.

        -  To assess the quality of life of patients with recurrent or progressive osteosarcoma
           undergoing treatment with avelumab, and to explore relationships between clinical
           factors and patient-reported health-related quality of life (HRQOL) outcomes.

      Exploratory Objectives:

        -  To explore factors associated with response in patients treated with avelumab after
           recurrent or progressive osteosarcoma (e.g. tumor PD-L1 expression).

        -  To measure parameters of immune activation including subsets of peripheral blood
           mononuclear cells (PBMCs) and serum markers of immune activation.

        -  To evaluate the role of T-cells in immune checkpoint blockade via measures of cell
           proliferation, co-inhibitory receptor expression on CD8 T cells, T cell repertoire, and
           epigenetic programming.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must be > 12 years of age but < 50 years of age at the time of enrollment.

          -  Patients must have histologic verification of osteosarcoma at initial diagnosis or
             relapse.

          -  Patients must have had evidence of having relapsed, progressed or become refractory to
             conventional therapy.

          -  Patients must have measurable disease, documented by clinical, radiographic or
             histologic criteria. Disease must be bi-dimensionally measurable by computed
             tomography (CT) or magnetic resonance imaging (MRI).

          -  Patients must have a performance status of ≥ 50 using the Karnofsky scale for patients
             > 16 years of age and the Lansky scale for patients ≤ 16 years of age.

          -  Patients must have a life expectancy of ≥ 6 weeks.

          -  Patients must have fully recovered from the acute toxic effects of all prior
             chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

               1. Myelosuppressive chemotherapy: must not have received within 3 weeks of entry
                  onto this study.

               2. Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy
                  with a biologic agent.

               3. Immunotherapies: at least 42 days must have elapsed since a prior therapy that
                  included a monoclonal antibody or any other type of immunotherapy (e.g. chimeric
                  antigen receptor (CAR) T cell therapy).

               4. Radiation therapy (RT): ≥ 2 weeks for local palliative RT (small port); ≥ 6
                  months must have elapsed if prior craniospinal RT or if ≥ 50% radiation of the
                  pelvis; ≥ 6 weeks must have elapsed if other substantial bone marrow (BM)
                  radiation.

          -  Organ Function Requirements:

               1. Adequate bone marrow function defined as:

                    -  Peripheral absolute neutrophil count (ANC) ≥ 1500/mm3

                    -  Platelet count ≥ 100,000/mm3 (transfusion independent)

                    -  Hemoglobin ≥ 9.0 g/dL (may receive RBC transfusions)

               2. Adequate renal function defined as:

                    -  Creatinine clearance or radioisotope GFR ≥70 mL/min/1.73m2 OR

                    -  Serum creatinine based on age/gender as follows: (threshold creatinine
                       values were derived from the Schwartz formula for estimating GFR).

                         -  Age is: 12 to <13 years, then maximum creatinine is 1.2 mg/DL for male
                            and female.

                         -  Age is: 13 to <16 years, then maximum creatinine is 1.5 mg/DL for male
                            and 1.4 mg/DL for female.

                         -  Age is: ≥16 years, then maximum creatinine is 1.7 mg/DL for male and
                            1.4 mg/DL for female.

               3. Adequate liver function defined as:

                    -  Total Bilirubin ≤ 1.5x the institutional upper limit of normal (IULN) for
                       age

                    -  ALT (SGPT) and AST (SGOT) < 2.5 x IULN for age (or < 5 x IULN for patients
                       with documented metastatic disease to the liver)

                    -  Serum albumin > 2 g/dL

               4. Serum lipase ≤ upper limit of normal (IULN).

               5. Patients must have documented pulse oximetry ≥ 92% on room air.

          -  Female patients of childbearing potential must have a negative serum or urine
             pregnancy test within 7 days of enrollment.

          -  Male or female patients who are sexually active and of reproductive potential must
             agree to use an effective contraceptive method throughout the study and for at least
             60 days after last avelumab treatment administration. Abstinence is an acceptable form
             of contraception.

          -  Patients must not currently be using other investigational agents.

          -  Patients must not currently be using other anti-cancer agent.

          -  Patients must be able to comply with the safety monitoring of the study in the opinion
             of the investigator.

          -  Written, informed consent and assent following Institutional Review Board, NCI, FDA
             and OHRP guidelines.

        Exclusion Criteria:

          -  Central nervous system (CNS) metastases.

          -  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).

          -  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.

          -  Active infection requiring systemic therapy.

          -  Known history of testing positive for HIV or known acquired immunodeficiency syndrome.

          -  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).

          -  Patient who has received vaccination within 4 weeks of the first dose of avelumab and
             while on trials is prohibited except for administration of inactivated vaccines.

          -  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).

          -  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, see Appendix II), or serious cardiac arrhythmia
             requiring medication.

          -  Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however,
             alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety
             risk based on investigator's judgment are acceptable

          -  Other severe acute or chronic medical conditions including colitis, inflammatory bowel
             disease, pneumonitis, pulmonary fibrosis 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.

          -  Patients with active diarrhea > CTCAE v4.03 Grade 2.

          -  Patients who have previously received a prior organ transplantation, including
             allogeneic stem cell transplantation.

          -  Female patients who are pregnant or actively breastfeeding.

          -  Patients who have previously received anti-PD1 or anti-PD-L1 therapy. Patients who
             have previously received anti-CTLA-4 therapy (e.g. ipilimumab) are eligible for study.