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A Phase II Trial of Avelumab in Patients With Recurrent or Progressive Osteosarcoma

NCT03006848

Description:

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.

Related Conditions:
  • Osteosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II Trial of Avelumab in Patients With Recurrent or Progressive Osteosarcoma
  • Official Title: A Phase II Trial of Avelumab, A Fully Humanized Antibody That Targets Cells Expressing PD-L1, in Patients With Recurrent or Progressive Osteosarcoma

Clinical Trial IDs

  • ORG STUDY ID: OSTPDL1
  • SECONDARY ID: NCI-2016-02036
  • NCT ID: NCT03006848

Conditions

  • Osteosarcoma

Interventions

DrugSynonymsArms
AvelumabMSB0010718C, anti-PD-L1Avelumab

Purpose

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. 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.

Detailed Description

      This is a Phase 2 study using a traditional Simon two-stage design. Patients 12 years or
      greater with recurrent/refractory osteosarcoma 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. Progression free survival and response to therapy after 4 cycles of treatment will
      be assessed. In addition, the toxicity profile of avelumab in this population will be
      closely monitored.
    

Trial Arms

NameTypeDescriptionInterventions
AvelumabExperimentalAll participants with recurrent/refractory osteosarcoma who consent to the study.
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be > 12 years of age but < 50 years of age at the time of enrollment.

          -  Patients must have a diagnosis of recurrent or progressive osteosarcoma.

          -  Patients must have histologic verification of osteosarcoma at initial diagnosis.

          -  Patients must have had evidence of recurrence or progressive disease documented
             within 2 weeks of entry onto study.

          -  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.
      
Maximum Eligible Age:49 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:At the end of 4 cycles of avelumab (approximately 4 months after last participant enrollment)
Safety Issue:
Description:The study is designed by treating RECIST response [complete response + partial response (CR+PR)] after 4-cycle treatment of avelumab and the 16-week progression-free survival (PFS) as dual binary endpoints. Patients who fail to be evaluated at the end of the 4-cycle will be counted as failure.

Secondary Outcome Measures

Measure:Target toxicities
Time Frame:At the end of treatment (up to 2 years after enrollment of last participant)
Safety Issue:
Description:Target toxicities for avelumab treatment are defined as any grade 3-5 dyspnea, infusion-related reactions, or immune related adverse events at least possibly attributable to the agent observed anytime during the 26-cycle treatment period that a patient is on study (including the period between off treatment and off study).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Last Updated

March 30, 2017