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

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ClinicalTrials.gov Identifier: NCT03006848
Recruitment Status : Recruiting
First Posted : December 30, 2016
Last Update Posted : June 6, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Pfizer
Gateway for Cancer Research
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Tracking Information
First Submitted Date  ICMJE December 22, 2016
First Posted Date  ICMJE December 30, 2016
Last Update Posted Date June 6, 2019
Actual Study Start Date  ICMJE February 16, 2017
Estimated Primary Completion Date May 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 27, 2016)
  • Response rate [ Time Frame: At the end of 4 cycles of avelumab (approximately 4 months after last participant enrollment) ]
    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.
  • Progression-free survival [ Time Frame: At the end of 4 cycles of avelumab (approximately 4 months after last participant enrollment) ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03006848 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 27, 2016)
Target toxicities [ Time Frame: At the end of treatment (up to 2 years after enrollment of last participant) ]
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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 22, 2017)
  • Factors associated with response [ Time Frame: Following completion of therapy for last participant (up to 2 years after enrollment) ]
    Logistic regression analysis will be conducted to explore factors which may associate with response.
  • Change in parameters of immune activation [ Time Frame: Baseline prior to start of therapy and following 2 cycles of therapy (up to 8 weeks after last enrollment) ]
    Descriptive statistics will be provided.
  • Change in cell proliferation [ Time Frame: Baseline prior to start of therapy and after completion of therapy (approximately 2 years after last participant enrollment). ]
    Descriptive statistics will be provided.
  • Change in co-inhibitory receptor expression on CD8 T cells [ Time Frame: Baseline prior to start of therapy and after completion of therapy (approximately 2 years after last participant enrollment). ]
    Descriptive statistics will be provided.
  • Change in Quality of Life [ Time Frame: From baseline prior to start of treatment through the end of avelumab therapy (up to approximately 2 years) ]
    Participants will self-report their quality of life through PROMIS questionnaires, either the Pediatric Profile (ages 8 to 17 years) or the Adult Profile (age 18 years or older). The change in age-normed T-scores will be reported. Mixed effect models will be performed to assess changes in quality of life over time.
Original Other Pre-specified Outcome Measures
 (submitted: December 27, 2016)
  • Factors associated with response [ Time Frame: Following completion of therapy for last participant (up to 2 years after enrollment) ]
    Logistic regression analysis will be conducted to explore factors which may associate with response.
  • Change in parameters of immune activation [ Time Frame: Baseline prior to start of therapy and following 2 cycles of therapy (up to 8 weeks after last enrollment) ]
    Descriptive statistics will be provided.
  • Change in cell proliferation [ Time Frame: Baseline prior to start of therapy and after completion of therapy (approximately 2 years after last participant enrollment). ]
    Descriptive statistics will be provided.
  • Change in co-inhibitory receptor expression on CD8 T cells [ Time Frame: Baseline prior to start of therapy and after completion of therapy (approximately 2 years after last participant enrollment). ]
    Descriptive statistics will be provided.
 
Descriptive Information
Brief Title  ICMJE A Phase II Trial of Avelumab in Patients With Recurrent or Progressive Osteosarcoma
Official Title  ICMJE A Phase II Trial of Avelumab, A Fully Human Antibody That Targets Cells Expressing PD-L1, in Patients With Recurrent or Progressive Osteosarcoma
Brief 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Osteosarcoma
Intervention  ICMJE
  • Drug: Avelumab
    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.
    Other Names:
    • MSB0010718C
    • anti-PD-L1
  • Other: Questionnaires
    To assess quality of life, patients will complete questionnaires at four time points.
    Other Names:
    • PROMIS Pediatric Profile
    • PROMIS Adult Profile
Study Arms  ICMJE Experimental: Avelumab

All participants with recurrent/refractory osteosarcoma who consent to the study.

Interventions: Avelumab and quality of life questionnaires.

Interventions:
  • Drug: Avelumab
  • Other: Questionnaires
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 27, 2016)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2023
Estimated Primary Completion Date May 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 49 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michael W. Bishop, MD, MS 866-278-5833 referralinfo@stjude.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03006848
Other Study ID Numbers  ICMJE OSTPDL1
NCI-2016-02036 ( Registry Identifier: NCI Clinical Trial Registration Program )
Pfizer W1211733 (OSTPDL1) ( Other Grant/Funding Number: Pfizer, Inc. )
Gateway RESAG ( Other Grant/Funding Number: Gateway for Cancer Research )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party St. Jude Children's Research Hospital
Study Sponsor  ICMJE St. Jude Children's Research Hospital
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Pfizer
  • Gateway for Cancer Research
Investigators  ICMJE
Principal Investigator: Michael W. Bishop, MD, MS St. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP