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

• ClinicalTrials.gov Identifier: NCT03006848
• Recruitment Status: Active, not recruiting
• First Posted: December 30, 2016
• Results First Posted: September 16, 2021
• Last Update Posted: August 23, 2022
• Sponsor: St. Jude Children's Research Hospital
• Collaborators: National Cancer Institute (NCI); Pfizer; Gateway for Cancer Research
• Information provided by (Responsible Party): St. Jude Children's Research Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Osteosarcoma	Drug: Avelumab; Other: Questionnaires	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Avelumab, A Fully Human Antibody That Targets Cells Expressing PD-L1, in Patients With Recurrent or Progressive Osteosarcoma
• Actual Study Start Date: February 16, 2017
• Actual Primary Completion Date: March 18, 2020
• Estimated Study Completion Date: January 31, 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Avelumab; All participants with recurrent/refractory osteosarcoma who consent to the study. Interventions: Avelumab and quality of life questionnaires.

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

Outcome Measures

Primary Outcome Measures :

1. Response Rate [ Time Frame: At the end of 4 cycles of avelumab (approximately 4 months) ]
   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.
2. Progression-free Survival [ Time Frame: At the end of 4 cycles of avelumab (approximately 4 months) ]
   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 :

1. 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).

Other Outcome Measures:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 49 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

United States, Tennessee

St Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

United States, Texas

Texas Children's Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

St. Jude Children's Research Hospital

National Cancer Institute (NCI)

Pfizer

Gateway for Cancer Research

Investigators

• Principal Investigator: Michael W. Bishop, MD, MS; St. Jude Children's Research Hospital

  Study Documents (Full-Text)

Documents provided by St. Jude Children's Research Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] June 26, 2019

More Information

Additional Information:

St. Jude Children's Research Hospital 

Clinical Trials Open at St. Jude 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT03006848
• Other Study ID Numbers: 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 )
• First Posted: December 30, 2016
• Results First Posted: September 16, 2021
• Last Update Posted: August 23, 2022
• Last Verified: August 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Jude Children's Research Hospital:

Osteosarcoma; PD-L1; Immunotherapy

Additional relevant MeSH terms:

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Avelumab; Antineoplastic Agents, Immunological; Antineoplastic Agents