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Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma

Sponsor
Children's Oncology Group (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02470091
Collaborator
National Cancer Institute (NCI) (NIH)
56
Enrollment
141
Locations
1
Arm
82.7
Anticipated Duration (Months)
0.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: Denosumab
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
 Phase 2

Detailed Description

PRIMARY OBJECTIVES:

  1. 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).

  2. 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:

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

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

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

  4. 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 monthly for 1 year.

Study Design

Study Type:
Interventional
Actual Enrollment :
56 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 2 Study of Denosumab (NSC# 744010), a RANK Ligand Antibody, for Recurrent or Refractory Osteosarcoma
Actual Study Start Date :
Nov 9, 2015
Actual Primary Completion Date :
Dec 31, 2019
Anticipated Study Completion Date :
Sep 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (denosumab)

Patients 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.

Biological: Denosumab
Given SC
Other Names:
  • AMG 162
  • AMG-162
  • Denosumab Biosimilar TK-006
  • Prolia
  • TK-006
  • Xgeva

    • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Disease Control Rate (Cohort I) [At 4 months]

      Disease control interval was calculated as the time from enrolment until detection of new disease or progression of an existing site of disease as determined by the treating physician. Disease control interval of at least 4 months was considered disease control success.

    2. Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I) [At 4 months]

      Per Response Evaluation Criteria In Solid TumorsCriteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response(CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

    3. Disease Control Rate (Cohort II) [At 12 months]

      Disease control interval was calculated as the time from enrolment until detection of new disease as determined by the treating physician. Disease control interval of at least 12 months was considered disease control success.

    Secondary Outcome Measures

    1. Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab [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]

      Sample means of trough concentrations of denosumab will be calculated.

    2. Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab [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]

      Sample medians of trough concentrations of denosumab will be calculated.

    3. Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide [Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7]

      Serum c-telopeptide in pg/ml

    4. Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio [Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7]

      Urine n-telopeptide to creatinine ratio expressed as nMol BCE/mmol creatinine

    5. Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [Minimum of 2 years]

      The number of cycles where a dose-limiting toxicity was identified where dose-limiting toxicity is defined in the protocol using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

    6. Response Rate (CR or PR) for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) [Up to 3 years post-treatment]

      Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.

    7. Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) [At 4 months]

      Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.

    8. Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II) [At 12 months]

      Disease control interval was calculated at the time from enrolment until detection of new disease as determined by the treating physician. The proportion of patients who experience disease control of at least 12 months will be estimated by the method of Kaplan and Meier.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    11 Years to 49 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    • 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

    • Note: This applies if AOST1421 is open to enrollment at the enrolling institution on the day the patient consents

    • 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)

    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 mg/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 or planned invasive dental procedures during the anticipated course of study therapy

    • 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 while on study therapy and through 5 months after completion of study therapy

    • 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

    • 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 Phoenix Childrens Hospital Phoenix Arizona United States 85016
    3 Banner University Medical Center - Tucson Tucson Arizona United States 85719
    4 Arkansas Children's Hospital Little Rock Arkansas United States 72202-3591
    5 Kaiser Permanente-Anaheim Anaheim California United States 92806
    6 Kaiser Permanente-Bellflower Bellflower California United States 90706
    7 Kaiser Permanente Downey Medical Center Downey California United States 90242
    8 Kaiser Permanente-Fontana Fontana California United States 92335
    9 Loma Linda University Medical Center Loma Linda California United States 92354
    10 Children's Hospital Los Angeles Los Angeles California United States 90027
    11 Kaiser Permanente Los Angeles Medical Center Los Angeles California United States 90027
    12 Valley Children's Hospital Madera California United States 93636
    13 Children's Hospital and Research Center at Oakland Oakland California United States 94609-1809
    14 Children's Hospital of Orange County Orange California United States 92868
    15 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    16 Kaiser Permanente-San Diego Zion San Diego California United States 92120
    17 Rady Children's Hospital - San Diego San Diego California United States 92123
    18 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    19 Children's Hospital Colorado Aurora Colorado United States 80045
    20 Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver Colorado United States 80218
    21 Connecticut Children's Medical Center Hartford Connecticut United States 06106
    22 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    23 Children's National Medical Center Washington District of Columbia United States 20010
    24 University of Florida Health Science Center - Gainesville Gainesville Florida United States 32610
    25 Nemours Children's Clinic-Jacksonville Jacksonville Florida United States 32207
    26 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    27 Nicklaus Children's Hospital Miami Florida United States 33155
    28 AdventHealth Orlando Orlando Florida United States 32803
    29 Nemours Children's Hospital Orlando Florida United States 32827
    30 Johns Hopkins All Children's Hospital Saint Petersburg Florida United States 33701
    31 Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida United States 33607
    32 Saint Mary's Hospital West Palm Beach Florida United States 33407
    33 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    34 Kapiolani Medical Center for Women and Children Honolulu Hawaii United States 96826
    35 Saint Luke's Mountain States Tumor Institute Boise Idaho United States 83712
    36 Centralia Oncology Clinic Centralia Illinois United States 62801
    37 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    38 University of Illinois Chicago Illinois United States 60612
    39 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    40 Carle on Vermilion Danville Illinois United States 61832
    41 Cancer Care Specialists of Illinois - Decatur Decatur Illinois United States 62526
    42 Carle Physician Group-Effingham Effingham Illinois United States 62401
    43 Crossroads Cancer Center Effingham Illinois United States 62401
    44 Carle Physician Group-Mattoon/Charleston Mattoon Illinois United States 61938
    45 Cancer Care Center of O'Fallon O'Fallon Illinois United States 62269
    46 Saint Jude Midwest Affiliate Peoria Illinois United States 61637
    47 Carle Cancer Center Urbana Illinois United States 61801
    48 The Carle Foundation Hospital Urbana Illinois United States 61801
    49 Riley Hospital for Children Indianapolis Indiana United States 46202
    50 Saint Vincent Hospital and Health Care Center Indianapolis Indiana United States 46260
    51 University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa United States 52242
    52 University of Kentucky/Markey Cancer Center Lexington Kentucky United States 40536
    53 Norton Children's Hospital Louisville Kentucky United States 40202
    54 Ochsner Medical Center Jefferson New Orleans Louisiana United States 70121
    55 Maine Children's Cancer Program Scarborough Maine United States 04074
    56 Sinai Hospital of Baltimore Baltimore Maryland United States 21215
    57 Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    58 Walter Reed National Military Medical Center Bethesda Maryland United States 20889-5600
    59 Brigham and Women's Hospital Boston Massachusetts United States 02115
    60 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    61 UMass Memorial Medical Center - University Campus Worcester Massachusetts United States 01655
    62 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    63 Wayne State University/Karmanos Cancer Institute Detroit Michigan United States 48201
    64 Ascension Saint John Hospital Detroit Michigan United States 48236
    65 Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan United States 49503
    66 Bronson Methodist Hospital Kalamazoo Michigan United States 49007
    67 Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota United States 55404
    68 University of Minnesota/Masonic Cancer Center Minneapolis Minnesota United States 55455
    69 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    70 University of Mississippi Medical Center Jackson Mississippi United States 39216
    71 Children's Mercy Hospitals and Clinics Kansas City Missouri United States 64108
    72 Washington University School of Medicine Saint Louis Missouri United States 63110
    73 Mercy Hospital Saint Louis Saint Louis Missouri United States 63141
    74 Children's Hospital and Medical Center of Omaha Omaha Nebraska United States 68114
    75 University of Nebraska Medical Center Omaha Nebraska United States 68198
    76 Sunrise Hospital and Medical Center Las Vegas Nevada United States 89109
    77 Alliance for Childhood Diseases/Cure 4 the Kids Foundation Las Vegas Nevada United States 89135
    78 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
    79 Hackensack University Medical Center Hackensack New Jersey United States 07601
    80 Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital New Brunswick New Jersey United States 08903
    81 Rutgers Cancer Institute of New Jersey New Brunswick New Jersey United States 08903
    82 Newark Beth Israel Medical Center Newark New Jersey United States 07112
    83 University of New Mexico Cancer Center Albuquerque New Mexico United States 87102
    84 Albany Medical Center Albany New York United States 12208
    85 Roswell Park Cancer Institute Buffalo New York United States 14263
    86 Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York United States 10016
    87 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    88 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    89 University of Rochester Rochester New York United States 14642
    90 State University of New York Upstate Medical University Syracuse New York United States 13210
    91 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    92 Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina United States 28203
    93 Wake Forest University Health Sciences Winston-Salem North Carolina United States 27157
    94 Sanford Broadway Medical Center Fargo North Dakota United States 58122
    95 Children's Hospital Medical Center of Akron Akron Ohio United States 44308
    96 UHHS-Chagrin Highlands Medical Center Beachwood Ohio United States 44122
    97 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    98 Case Western Reserve University Cleveland Ohio United States 44106
    99 Rainbow Babies and Childrens Hospital Cleveland Ohio United States 44106
    100 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    101 Nationwide Children's Hospital Columbus Ohio United States 43205
    102 Dayton Children's Hospital Dayton Ohio United States 45404
    103 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    104 Oregon Health and Science University Portland Oregon United States 97239
    105 Penn State Children's Hospital Hershey Pennsylvania United States 17033
    106 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    107 Children's Oncology Group Philadelphia Pennsylvania United States 19104
    108 Saint Christopher's Hospital for Children Philadelphia Pennsylvania United States 19134
    109 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    110 Rhode Island Hospital Providence Rhode Island United States 02903
    111 Medical University of South Carolina Charleston South Carolina United States 29425
    112 Prisma Health Richland Hospital Columbia South Carolina United States 29203
    113 Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota United States 57117-5134
    114 Saint Jude Children's Research Hospital Memphis Tennessee United States 38105
    115 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    116 Dell Children's Medical Center of Central Texas Austin Texas United States 78723
    117 Driscoll Children's Hospital Corpus Christi Texas United States 78411
    118 Medical City Dallas Hospital Dallas Texas United States 75230
    119 UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas United States 75390
    120 Cook Children's Medical Center Fort Worth Texas United States 76104
    121 Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas United States 77030
    122 Children's Hospital of San Antonio San Antonio Texas United States 78207
    123 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    124 Primary Children's Hospital Salt Lake City Utah United States 84113
    125 University of Vermont and State Agricultural College Burlington Vermont United States 05405
    126 University of Virginia Cancer Center Charlottesville Virginia United States 22908
    127 Children's Hospital of The King's Daughters Norfolk Virginia United States 23507
    128 Virginia Commonwealth University/Massey Cancer Center Richmond Virginia United States 23298
    129 Seattle Children's Hospital Seattle Washington United States 98105
    130 Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington United States 99204
    131 West Virginia University Healthcare Morgantown West Virginia United States 26506
    132 Children's Hospital of Wisconsin Milwaukee Wisconsin United States 53226
    133 University of Alberta Hospital Edmonton Alberta Canada T6G 2B7
    134 IWK Health Centre Halifax Nova Scotia Canada B3K 6R8
    135 McMaster Children's Hospital at Hamilton Health Sciences Hamilton Ontario Canada L8N 3Z5
    136 Children's Hospital London Ontario Canada N6A 5W9
    137 Hospital for Sick Children Toronto Ontario Canada M5G 1X8
    138 The Montreal Children's Hospital of the MUHC Montreal Quebec Canada H3H 1P3
    139 Centre Hospitalier Universitaire de Quebec Quebec Canada G1V 4G2
    140 San Jorge Children's Hospital San Juan Puerto Rico 00912
    141 University Pediatric Hospital San Juan Puerto Rico 00926

    Sponsors and Collaborators

    • Children's Oncology Group
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Katherine A Janeway, Children's Oncology Group

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT02470091
    Other Study ID Numbers:
    • AOST1321
    • NCI-2015-00543
    • s15-01360
    • AOST1321
    • AOST1321
    • AOST1321
    • U10CA180886
    First Posted:
    Jun 12, 2015
    Last Update Posted:
    Apr 28, 2022
    Last Verified:
    Apr 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Osteosarcoma
    Recurrence
    Denosumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Cohort 1: Measurable Cohort 2: Resection
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    Period Title: Overall Study
    STARTED 16 40
    Follow-up Report 1 10
    COMPLETED 15 38
    NOT COMPLETED 1 2

    Baseline Characteristics

    Arm/Group Title Cohort 1: Measurable Cohort 2: Resection Total
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment Total of all reporting groups
    Overall Participants 16 40 56
    Age (Count of Participants)
    <=18 years
    16
    100%
    26
    65%
    42
    75%
    Between 18 and 65 years
    0
    0%
    14
    35%
    14
    25%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    15
    17
    16
    Sex: Female, Male (Count of Participants)
    Female
    5
    31.3%
    17
    42.5%
    22
    39.3%
    Male
    11
    68.8%
    23
    57.5%
    34
    60.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    5
    31.3%
    7
    17.5%
    12
    21.4%
    Not Hispanic or Latino
    10
    62.5%
    32
    80%
    42
    75%
    Unknown or Not Reported
    1
    6.3%
    1
    2.5%
    2
    3.6%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    6.3%
    0
    0%
    1
    1.8%
    Asian
    1
    6.3%
    1
    2.5%
    2
    3.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    6.3%
    2
    5%
    3
    5.4%
    White
    10
    62.5%
    32
    80%
    42
    75%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    3
    18.8%
    5
    12.5%
    8
    14.3%
    Region of Enrollment (participants) [Number]
    United States
    16
    100%
    39
    97.5%
    55
    98.2%
    Canada
    0
    0%
    1
    2.5%
    1
    1.8%

    Outcome Measures

    1. Primary Outcome
    Title Disease Control Rate (Cohort I)
    Description Disease control interval was calculated as the time from enrolment until detection of new disease or progression of an existing site of disease as determined by the treating physician. Disease control interval of at least 4 months was considered disease control success.
    Time Frame At 4 months

    Outcome Measure Data

    Analysis Population Description
    1 patient was excluded due to withdrawal.
    Arm/Group Title Cohort 1: Measurable
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
    Measure Participants 15
    Number [participants]
    1
    6.3%
    2. Primary Outcome
    Title Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I)
    Description Per Response Evaluation Criteria In Solid TumorsCriteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response(CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    Time Frame At 4 months

    Outcome Measure Data

    Analysis Population Description
    1 patient was excluded due to withdrawal.
    Arm/Group Title Cohort 1: Measurable
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
    Measure Participants 15
    Number [participants]
    0
    0%
    3. Primary Outcome
    Title Disease Control Rate (Cohort II)
    Description Disease control interval was calculated as the time from enrolment until detection of new disease as determined by the treating physician. Disease control interval of at least 12 months was considered disease control success.
    Time Frame At 12 months

    Outcome Measure Data

    Analysis Population Description
    2 patients were excluded due to ineligibility
    Arm/Group Title Cohort 2: Resection
    Arm/Group Description Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    Measure Participants 38
    Number [participants]
    10
    62.5%
    4. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab
    Description Sample means of trough concentrations of denosumab will be calculated.
    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

    Outcome Measure Data

    Analysis Population Description
    The number of patients who contributed samples varied across cycles.
    Arm/Group Title Cohort 1: Measurable Cohort 2: Resection
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    Measure Participants 15 27
    Serum denosumab (ng/ml): Cycle 1, Day 1
    0
    (0)
    0
    (0)
    Serum denosumab (ng/ml): Cycle 1, Day 8
    11.59
    (3.836665219)
    10.81
    (4.514421336)
    Serum denosumab (ng/ml): Cycle 1, Day 15
    20.57
    (8.290958931)
    22.07
    (10.0339424)
    Serum denosumab (ng/ml): Cycle 1, Day 22
    31.8
    (12.85573802)
    31.56
    (13.41044369)
    Serum denosumab (ng/ml): Cycle 2, Day 1
    30.57
    (10.78239306)
    30.28
    (11.77497346)
    Serum denosumab (ng/ml): Cycle 3, Day 1
    23.8
    (NA)
    27.49
    (13.31277582)
    Serum denosumab (ng/ml): Cycle 4, Day 1
    23.7
    (NA)
    23.67
    (11.83849653)
    Serum denosumab (ng/ml): Cycle 6, Day 1
    20.3
    (NA)
    31.22
    (14.57292009)
    Serum denosumab (ng/ml): Cycle 6, Day 15
    23.2
    (NA)
    26.66
    (11.95742447)
    Serum denosumab (ng/ml): Cycle 7, Day 1
    30.22
    (13.89748179)
    5. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab
    Description Sample medians of trough concentrations of denosumab will be calculated.
    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

    Outcome Measure Data

    Analysis Population Description
    The number of patients who contributed samples varied across cycles.
    Arm/Group Title Cohort 1: Measurable Cohort 2: Resection
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    Measure Participants 15 27
    Serum denosumab (ng/ml): Cycle 1, Day 1
    0
    0
    Serum denosumab (ng/ml): Cycle 1, Day 8
    10.8
    9.34
    Serum denosumab (ng/ml): Cycle 1, Day 15
    20.7
    18.75
    Serum denosumab (ng/ml): Cycle 1, Day 22
    27.85
    27.6
    Serum denosumab (ng/ml): Cycle 2, Day 1
    30.75
    27.3
    Serum denosumab (ng/ml): Cycle 3, Day 1
    23.8
    22.8
    Serum denosumab (ng/ml): Cycle 4, Day 1
    23.7
    21.6
    Serum denosumab (ng/ml): Cycle 6, Day 1
    20.3
    32.05
    Serum denosumab (ng/ml): Cycle 6, Day 15
    23.2
    23.5
    Serum denosumab (ng/ml): Cycle 7, Day 1
    27.95
    6. Secondary Outcome
    Title Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide
    Description Serum c-telopeptide in pg/ml
    Time Frame Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7

    Outcome Measure Data

    Analysis Population Description
    All eligible participants
    Arm/Group Title Cohort 1: Measurable Cohort 2: Resection
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    Measure Participants 15 38
    Serum c-telopeptide (pg/ml): Cycle 1, Day 1
    1713
    (1857)
    944.5
    (543)
    Serum c-telopeptide (pg/ml): Cycle 1, Day 8
    220.5
    (77)
    244.0625
    (259)
    Serum c-telopeptide (pg/ml): Cycle 1, Day 15
    203.1818
    (68)
    171.24
    (86)
    Serum c-telopeptide (pg/ml): Cycle 1, Day 22
    210.8889
    (95)
    178.5033
    (96)
    Serum c-telopeptide (pg/ml): Cycle 2, Day 1
    200.8
    (78)
    152.2032
    (61)
    Serum c-telopeptide (pg/ml): Cycle 3, Day 1
    115
    147.8818
    (85)
    Serum c-telopeptide (pg/ml): Cycle 4, Day 1
    116
    137.0235
    (80)
    Serum c-telopeptide (pg/ml): Cycle 7, Day 1
    108
    168.9
    (81)
    7. Secondary Outcome
    Title Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio
    Description Urine n-telopeptide to creatinine ratio expressed as nMol BCE/mmol creatinine
    Time Frame Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7

    Outcome Measure Data

    Analysis Population Description
    All eligible participants
    Arm/Group Title Cohort 1: Measurable Cohort 2: Resection
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    Measure Participants 15 38
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 1
    322.2
    (307)
    190.7714
    (283)
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 8
    30.36364
    (20)
    34.1875
    (35)
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 15
    26.18182
    (14)
    32.3
    (36)
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 22
    26.55556
    (19)
    32.16129
    (40)
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 2, Day 1
    22.1
    (15)
    28.42857
    (45)
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 3, Day 1
    14
    24.7619
    (20)
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 4, Day 1
    20
    29.29412
    (31)
    Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 7, Day 1
    13
    22.4
    (18)
    8. Secondary Outcome
    Title Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
    Description The number of cycles where a dose-limiting toxicity was identified where dose-limiting toxicity is defined in the protocol using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
    Time Frame Minimum of 2 years

    Outcome Measure Data

    Analysis Population Description
    56 patients were treated on protocol therapy. Three hundred seventy-three cycles were reported for the analysis of dose limiting toxicity
    Arm/Group Title Treatment (Denosumab)
    Arm/Group Description Patients 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.
    Measure Participants 56
    Measure cycles 373
    Number [cycles]
    1
    9. Secondary Outcome
    Title Response Rate (CR or PR) for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I)
    Description Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.
    Time Frame Up to 3 years post-treatment

    Outcome Measure Data

    Analysis Population Description
    There were not any patients that met criteria for bone site
    Arm/Group Title Cohort 1: Measurable
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
    Measure Participants 0
    10. Secondary Outcome
    Title Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I)
    Description Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.
    Time Frame At 4 months

    Outcome Measure Data

    Analysis Population Description
    There were not any patients that met criteria for bone site
    Arm/Group Title Cohort 1: Measurable
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
    Measure Participants 0
    11. Secondary Outcome
    Title Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II)
    Description Disease control interval was calculated at the time from enrolment until detection of new disease as determined by the treating physician. The proportion of patients who experience disease control of at least 12 months will be estimated by the method of Kaplan and Meier.
    Time Frame At 12 months

    Outcome Measure Data

    Analysis Population Description
    Patients that met criteria for bone site
    Arm/Group Title Cohort 2: Resection
    Arm/Group Description Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    Measure Participants 6
    Number (95% Confidence Interval) [proportion of patients]
    0.667

    Adverse Events

    Time Frame Through completion protocol therapy planned as 728 days after study enrollment
    Adverse Event Reporting Description Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
    Arm/Group Title Cohort 1: Measurable Cohort 2: Resection
    Arm/Group Description Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment
    All Cause Mortality
    Cohort 1: Measurable Cohort 2: Resection
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/15 (86.7%) 20/38 (52.6%)
    Serious Adverse Events
    Cohort 1: Measurable Cohort 2: Resection
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/15 (40%) 4/38 (10.5%)
    Blood and lymphatic system disorders
    Anemia 1/15 (6.7%) 1 1/38 (2.6%) 1
    Cardiac disorders
    Sinus tachycardia 1/15 (6.7%) 1 0/38 (0%) 0
    Gastrointestinal disorders
    Nausea 1/15 (6.7%) 1 0/38 (0%) 0
    Vomiting 1/15 (6.7%) 1 0/38 (0%) 0
    General disorders
    Fever 2/15 (13.3%) 2 0/38 (0%) 0
    Non-cardiac chest pain 1/15 (6.7%) 1 0/38 (0%) 0
    Infections and infestations
    Lung infection 1/15 (6.7%) 1 0/38 (0%) 0
    Investigations
    Weight loss 1/15 (6.7%) 1 0/38 (0%) 0
    Metabolism and nutrition disorders
    Anorexia 1/15 (6.7%) 1 0/38 (0%) 0
    Hypocalcemia 3/15 (20%) 3 0/38 (0%) 0
    Hypophosphatemia 1/15 (6.7%) 1 3/38 (7.9%) 3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 1/15 (6.7%) 1 0/38 (0%) 0
    Nervous system disorders
    Nervous system disorders - Other, specify 1/15 (6.7%) 1 0/38 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 3/15 (20%) 3 0/38 (0%) 0
    Hypoxia 1/15 (6.7%) 1 0/38 (0%) 0
    Pleural effusion 2/15 (13.3%) 2 1/38 (2.6%) 1
    Pleuritic pain 1/15 (6.7%) 1 0/38 (0%) 0
    Pulmonary edema 1/15 (6.7%) 1 0/38 (0%) 0
    Respiratory failure 1/15 (6.7%) 1 0/38 (0%) 0
    Vascular disorders
    Hematoma 0/15 (0%) 0 1/38 (2.6%) 1
    Thromboembolic event 1/15 (6.7%) 1 0/38 (0%) 0
    Other (Not Including Serious) Adverse Events
    Cohort 1: Measurable Cohort 2: Resection
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/15 (6.7%) 8/38 (21.1%)
    Investigations
    Lymphocyte count decreased 1/15 (6.7%) 1 0/38 (0%) 0
    Weight gain 0/15 (0%) 0 1/38 (2.6%) 1
    Metabolism and nutrition disorders
    Hypercalcemia 0/15 (0%) 0 1/38 (2.6%) 1
    Hyperglycemia 1/15 (6.7%) 1 0/38 (0%) 0
    Hypocalcemia 0/15 (0%) 0 1/38 (2.6%) 1
    Hypokalemia 0/15 (0%) 0 1/38 (2.6%) 1
    Hypophosphatemia 1/15 (6.7%) 1 6/38 (15.8%) 6
    Obesity 0/15 (0%) 0 1/38 (2.6%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Must obtain prior sponsor approval

    Results Point of Contact

    Name/Title Results Reporting Coordinator
    Organization Children's Oncology Group
    Phone 626-447-0064
    Email resultsreportingcoordinator@childrensoncologygroup.org
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT02470091
    Other Study ID Numbers:
    • AOST1321
    • NCI-2015-00543
    • s15-01360
    • AOST1321
    • AOST1321
    • AOST1321
    • U10CA180886
    First Posted:
    Jun 12, 2015
    Last Update Posted:
    Apr 28, 2022
    Last Verified:
    Apr 1, 2022