Clinical Trials /

Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma

NCT02470091

Description:

This phase II trial studies how well denosumab works in treating patients with osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as denosumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Osteosarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma
  • Official Title: Phase II Study of Denosumab (NSC# 744010), a RANK Ligand Antibody, for Recurrent or Refractory Osteosarcoma

Clinical Trial IDs

  • ORG STUDY ID: AOST1321
  • SECONDARY ID: NCI-2015-00543
  • SECONDARY ID: AOST1321
  • SECONDARY ID: AOST1321
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02470091

Conditions

  • Childhood Osteosarcoma
  • Metastatic Osteosarcoma
  • Recurrent Osteosarcoma

Interventions

DrugSynonymsArms
DenosumabAMG 162, AMG-162, Prolia, XgevaTreatment (denosumab)

Purpose

This phase II trial studies how well denosumab works in treating patients with osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory). Monoclonal antibodies, such as denosumab, may block tumor growth in different ways by targeting certain cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine whether denosumab therapy either increases the disease control rate at 4
      months in patients with recurrent measurable osteosarcoma as compared to historical
      Children's Oncology Group (COG) experience or denosumab therapy produces an objective
      response rate greater than 5% (Cohort 1).

      II. To determine whether denosumab therapy increases the disease control rate at 12 months in
      patients with recurrent resected osteosarcoma as compared to historical COG experience
      (Cohort 2).

      SECONDARY OBJECTIVES:

      I. To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab in
      subjects with recurrent osteosarcoma.

      II. To describe the tolerability of denosumab in subjects with recurrent osteosarcoma.

      III. To report the disease control rate and objective response rate for patients with
      recurrent osteosarcoma limited to bone.

      TERTIARY OBJECTIVES:

      I. To investigate biological markers potentially associated with response to denosumab in
      patients with recurrent osteosarcoma.

      OUTLINE:

      Patients receive denosumab subcutaneously (SC) on day 1 (days 1, 8, and 15 of course 1 only).
      Treatment repeats every 4 weeks (28 days) for up to 24 months or 26 courses, whichever occurs
      first, in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (denosumab)ExperimentalPatients receive denosumab SC on day 1 (days 1, 8, and 15 of course 1 only). Treatment repeats every 4 weeks (28 days) for up to 24 months or 26 courses, whichever occurs first, in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Female patients must have a bone age of equal to or greater than 12 years of age as
                 determined by local read of appropriate radiographic imaging
    
              -  Male patients must have a bone age of equal to or greater than 14 years of age as
                 determined by local read of appropriate radiographic imaging
    
              -  Patients must have relapsed or become refractory to conventional therapy, with a
                 regimen including some combination of high dose methotrexate, doxorubicin, cisplatin,
                 ifosfamide and etoposide; and have had histologic verification of osteosarcoma at
                 original diagnosis or at the time of recurrence
    
              -  Cohort 1 patients must have measurable disease according to Response Evaluation
                 Criteria In Solid Tumors (RECIST) 1.1
    
                   -  Note: Patients in Cohort 1 will be stratified as follows:
    
                        -  Stratum 1: Patients >= 11 years of age but < 18 years
    
                        -  Stratum 2: Patients >= 11 years of age but < 50 years
    
              -  Cohort 2 patients must have had a complete resection of all sites of metastatic
                 disease within 30 days prior to enrollment
    
                   -  Patients will only be eligible after they have undergone complete surgical
                      resection of suspected metastatic disease that is histopathologically confirmed
                      to be osteosarcoma prior to enrollment
    
                        -  Note: The definition of complete resections is: gross resection of all
                           disease as per the operating surgeon; post-operative imaging is not required
                           for confirmation of complete resection
    
                   -  Patients must undergo resection of any lung lesion meeting criteria for likely
                      metastatic disease, defined as:
    
                        -  3 or more lesions > 5 mm in diameter OR a single lesion > 1 cm
    
                   -  Patients with lung as the only site of resected metastatic disease must have
                      refused participation in protocol AOST1421
    
              -  Patient must have adequate tumor specimen available for submission
    
              -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
                 Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and
                 Lansky for patients =< 16 years of age
    
              -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
                 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
    
                   -  Age: 11 to < 13 years old; 1.2 (male, female) maximum serum creatinine (mg/dL)
    
                   -  Age: 13 to < 16 years old; 1.5 (male), 1.4 (female) maximum serum creatinine
                      (mg/dL)
    
                   -  Age: >= 16 years old; 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL)
    
              -  Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
    
              -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
                 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
                 ULN for age
    
              -  Serum calcium or albumin-adjusted serum calcium >= 2.0 mmol/L (8.0 mg/dL) and =< 2.9
                 mmol/L (11.5 mg/dL)
    
              -  All patients and/or their parents or legal guardians must sign a written informed
                 consent
    
              -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
                 (NCI) requirements for human studies must be met
    
            Exclusion Criteria:
    
              -  Patients with known sensitivity to any of the products to be administered during the
                 study (eg, mammalian derived products, calcium or vitamin D)
    
              -  Patients who are receiving other cancer directed therapy at the time of enrollment
    
              -  Patients who have previously received denosumab
    
              -  Patients who have previously received mithramycin, strontium-89, samarium-153 or
                 rhenium
    
              -  Patients receiving bisphosphonates
    
              -  Pre-existing conditions
    
                   -  Disorders associated with abnormal bone metabolism
    
                   -  Hypocalcemia that is not corrected with oral calcium supplementation
    
                   -  Vitamin D < 20 ng/mL
    
                   -  Paget's disease
    
                   -  Prior history or current evidence of osteonecrosis of the jaw
    
                   -  Any dental or oral condition likely to result in disruption of mucosal integrity
                      during denosumab therapy including: active dental or jaw condition requiring oral
                      surgery or tooth extraction; non-healed dental or oral surgery
    
                   -  Unstable systemic disease, excluding osteosarcoma, such as unstable proximal
                      renal tubule dysfunction (Fanconi Syndrome) or congestive heart failure
    
              -  Pregnancy and breast feeding
    
                   -  Female patients who are pregnant; a pregnancy test is required for female
                      patients of childbearing potential
    
                   -  Lactating females who plan to breastfeed their infants
    
                   -  Sexually active patients of reproductive potential who have not agreed to use an
                      effective contraceptive method for the duration of their study participation and
                      for 5 months after the end of study treatment
          
    Maximum Eligible Age:49 Years
    Minimum Eligible Age:11 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Disease control rate (Cohort I)
    Time Frame:At 4 months
    Safety Issue:
    Description:Compared to historical COG experience or denosumab therapy produces an objective response rate greater than 5%.

    Secondary Outcome Measures

    Measure:Disease control rates for patients with recurrent osteosarcoma limited to bone (Cohort I)
    Time Frame:At 4 months
    Safety Issue:
    Description:Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.
    Measure:Disease control rates for patients with recurrent osteosarcoma limited to bone (Cohort II)
    Time Frame:At 12 months
    Safety Issue:
    Description:The proportion of patients who experience 12 month disease control will be estimated by the method of Kaplan and Meier. The complementary log-log transformation of the Kaplan-Meier estimate of the 12 month disease control probability will be used to construct confidence intervals of that probability.
    Measure:Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
    Time Frame:Minimum of 2 years
    Safety Issue:
    Description:Will use a Bayesian rule to monitor for excessive toxicity. Descriptive analyses of this safety information will be performed and will include the incidence of adverse events, severe adverse events, serious adverse events, and fatal adverse events. Type, frequency, and severity of laboratory abnormalities will also be analyzed. Safety analyses will be performed in aggregate, by cohort, and by age group (=< 18 years and in patients > 18 years of age). The safety of denosumab in adults and adolescents will be compared.
    Measure:Modeling of PK parameters of denosumab
    Time Frame:Days 1, 8, 15, and 22 of course 1, day 1 of courses 2-4 and 7, and days 1 and 15 of course 6
    Safety Issue:
    Description:The presentation of PK values will be segregated according to time point at which the denosumab was administered.
    Measure:Modeling of PD parameters of denosumab
    Time Frame:Days 1, 8, 15, and 22 of course 1, day 1 of courses 2-4 and 7, and days 1 and 15 of course 6
    Safety Issue:
    Description:Sample means, medians and variances will be calculated. Clearance and volume of distribution will be determined. PD will be characterized by uNTx/Cr ratio and c-telopeptide levels. Both of these characteristics will be modeled according to a repeated measures linear regression model. Depending on the fit of the quadratic model, additional terms in powers of time since enrollment may be added to explore how the PD parameters vary with time.
    Measure:Response rate (CR or PR) for patients with recurrent osteosarcoma limited to bone (Cohort I)
    Time Frame:Up to 3 years post-treatment
    Safety Issue:
    Description:Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Children's Oncology Group

    Last Updated

    July 19, 2017