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

NCT03006848

Last updated date
Study Location
Children's Hospital Los Angeles
Los Angeles, California, 90027, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Osteosarcoma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
12-49 years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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.

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OsteosarcomaA Phase II Trial of Avelumab in Patients With Recurrent or Progressive Osteosarcoma
NCT03006848
  1. Los Angeles, California
  2. New York, New York
  3. Memphis, Tennessee
  4. Houston, Texas
ALL GENDERS
12 Years+
years
MULTIPLE SITES
Advanced Information
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 Allocation: N/A
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 * Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14. Review.

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 19, 2020)
15
Original Estimated Enrollment  ICMJE
 (submitted: December 27, 2016)
40
Estimated Study Completion Date  ICMJE January 31, 2023
Actual Primary Completion Date March 18, 2020   (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 information is only displayed when the study is recruiting subjects
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, MSSt. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date March 2020

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