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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02470091
Other study ID # AOST1321
Secondary ID NCI-2015-00543s1
Status Completed
Phase Phase 2
First received
Last updated
Start date November 21, 2015
Est. completion date December 31, 2023

Study information

Verified date January 2024
Source Children's Oncology Group
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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. IV. 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.


Recruitment information / eligibility

Status Completed
Enrollment 56
Est. completion date December 31, 2023
Est. primary completion date December 31, 2019
Accepts healthy volunteers No
Gender All
Age group 11 Years to 49 Years
Eligibility 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

Study Design


Intervention

Biological:
Denosumab
Given SC
Other:
Laboratory Biomarker Analysis
Correlative studies
Pharmacological Study
Correlative studies

Locations

Country Name City State
Canada University of Alberta Hospital Edmonton Alberta
Canada IWK Health Centre Halifax Nova Scotia
Canada McMaster Children's Hospital at Hamilton Health Sciences Hamilton Ontario
Canada Children's Hospital London Ontario
Canada The Montreal Children's Hospital of the MUHC Montreal Quebec
Canada CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL) Quebec
Canada Hospital for Sick Children Toronto Ontario
Puerto Rico San Jorge Children's Hospital San Juan
Puerto Rico University Pediatric Hospital San Juan
United States Children's Hospital Medical Center of Akron Akron Ohio
United States Albany Medical Center Albany New York
United States University of New Mexico Cancer Center Albuquerque New Mexico
United States Kaiser Permanente-Anaheim Anaheim California
United States C S Mott Children's Hospital Ann Arbor Michigan
United States Children's Healthcare of Atlanta - Egleston Atlanta Georgia
United States Children's Hospital Colorado Aurora Colorado
United States Dell Children's Medical Center of Central Texas Austin Texas
United States Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland
United States Sinai Hospital of Baltimore Baltimore Maryland
United States UHHS-Chagrin Highlands Medical Center Beachwood Ohio
United States Kaiser Permanente-Bellflower Bellflower California
United States Walter Reed National Military Medical Center Bethesda Maryland
United States Children's Hospital of Alabama Birmingham Alabama
United States Saint Luke's Cancer Institute - Boise Boise Idaho
United States Brigham and Women's Hospital Boston Massachusetts
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Roswell Park Cancer Institute Buffalo New York
United States University of Vermont and State Agricultural College Burlington Vermont
United States Centralia Oncology Clinic Centralia Illinois
United States UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina
United States Medical University of South Carolina Charleston South Carolina
United States Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina
United States University of Virginia Cancer Center Charlottesville Virginia
United States Lurie Children's Hospital-Chicago Chicago Illinois
United States University of Chicago Comprehensive Cancer Center Chicago Illinois
United States University of Illinois Chicago Illinois
United States Cincinnati Children's Hospital Medical Center Cincinnati Ohio
United States Case Western Reserve University Cleveland Ohio
United States Cleveland Clinic Foundation Cleveland Ohio
United States Rainbow Babies and Childrens Hospital Cleveland Ohio
United States Prisma Health Richland Hospital Columbia South Carolina
United States Nationwide Children's Hospital Columbus Ohio
United States Driscoll Children's Hospital Corpus Christi Texas
United States Medical City Dallas Hospital Dallas Texas
United States UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas
United States Carle at The Riverfront Danville Illinois
United States Dayton Children's Hospital Dayton Ohio
United States Cancer Care Specialists of Illinois - Decatur Decatur Illinois
United States Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver Colorado
United States Ascension Saint John Hospital Detroit Michigan
United States Wayne State University/Karmanos Cancer Institute Detroit Michigan
United States Kaiser Permanente Downey Medical Center Downey California
United States Carle Physician Group-Effingham Effingham Illinois
United States Crossroads Cancer Center Effingham Illinois
United States Sanford Broadway Medical Center Fargo North Dakota
United States Kaiser Permanente-Fontana Fontana California
United States Cook Children's Medical Center Fort Worth Texas
United States University of Florida Health Science Center - Gainesville Gainesville Florida
United States Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan
United States Hackensack University Medical Center Hackensack New Jersey
United States Connecticut Children's Medical Center Hartford Connecticut
United States Penn State Children's Hospital Hershey Pennsylvania
United States Kapiolani Medical Center for Women and Children Honolulu Hawaii
United States Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas
United States Ascension Saint Vincent Indianapolis Hospital Indianapolis Indiana
United States Riley Hospital for Children Indianapolis Indiana
United States University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa
United States University of Mississippi Medical Center Jackson Mississippi
United States Nemours Children's Clinic-Jacksonville Jacksonville Florida
United States Bronson Methodist Hospital Kalamazoo Michigan
United States Children's Mercy Hospitals and Clinics Kansas City Missouri
United States Alliance for Childhood Diseases/Cure 4 the Kids Foundation Las Vegas Nevada
United States Sunrise Hospital and Medical Center Las Vegas Nevada
United States Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center Lebanon New Hampshire
United States University of Kentucky/Markey Cancer Center Lexington Kentucky
United States Arkansas Children's Hospital Little Rock Arkansas
United States Loma Linda University Medical Center Loma Linda California
United States Children's Hospital Los Angeles Los Angeles California
United States Kaiser Permanente Los Angeles Medical Center Los Angeles California
United States Norton Children's Hospital Louisville Kentucky
United States Valley Children's Hospital Madera California
United States Carle Physician Group-Mattoon/Charleston Mattoon Illinois
United States Saint Jude Children's Research Hospital Memphis Tennessee
United States Nicklaus Children's Hospital Miami Florida
United States University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida
United States Children's Hospital of Wisconsin Milwaukee Wisconsin
United States Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota
United States University of Minnesota/Masonic Cancer Center Minneapolis Minnesota
United States West Virginia University Healthcare Morgantown West Virginia
United States Vanderbilt University/Ingram Cancer Center Nashville Tennessee
United States Rutgers Cancer Institute of New Jersey New Brunswick New Jersey
United States Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital New Brunswick New Jersey
United States Ochsner Medical Center Jefferson New Orleans Louisiana
United States Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York
United States Memorial Sloan Kettering Cancer Center New York New York
United States NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York
United States Newark Beth Israel Medical Center Newark New Jersey
United States Children's Hospital of The King's Daughters Norfolk Virginia
United States Cancer Care Center of O'Fallon O'Fallon Illinois
United States UCSF Benioff Children's Hospital Oakland Oakland California
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States Children's Hospital and Medical Center of Omaha Omaha Nebraska
United States University of Nebraska Medical Center Omaha Nebraska
United States Children's Hospital of Orange County Orange California
United States AdventHealth Orlando Orlando Florida
United States Nemours Children's Hospital Orlando Florida
United States Saint Jude Midwest Affiliate Peoria Illinois
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States Children's Oncology Group Philadelphia Pennsylvania
United States Saint Christopher's Hospital for Children Philadelphia Pennsylvania
United States Phoenix Childrens Hospital Phoenix Arizona
United States Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania
United States Oregon Health and Science University Portland Oregon
United States Rhode Island Hospital Providence Rhode Island
United States Virginia Commonwealth University/Massey Cancer Center Richmond Virginia
United States Mayo Clinic in Rochester Rochester Minnesota
United States University of Rochester Rochester New York
United States University of California Davis Comprehensive Cancer Center Sacramento California
United States Mercy Hospital Saint Louis Saint Louis Missouri
United States Washington University School of Medicine Saint Louis Missouri
United States Johns Hopkins All Children's Hospital Saint Petersburg Florida
United States Primary Children's Hospital Salt Lake City Utah
United States Children's Hospital of San Antonio San Antonio Texas
United States University of Texas Health Science Center at San Antonio San Antonio Texas
United States Kaiser Permanente-San Diego Zion San Diego California
United States Rady Children's Hospital - San Diego San Diego California
United States UCSF Medical Center-Mission Bay San Francisco California
United States Maine Children's Cancer Program Scarborough Maine
United States Seattle Children's Hospital Seattle Washington
United States Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota
United States Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington
United States State University of New York Upstate Medical University Syracuse New York
United States Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida
United States Banner University Medical Center - Tucson Tucson Arizona
United States Carle Cancer Center Urbana Illinois
United States The Carle Foundation Hospital Urbana Illinois
United States Children's National Medical Center Washington District of Columbia
United States Saint Mary's Hospital West Palm Beach Florida
United States Alfred I duPont Hospital for Children Wilmington Delaware
United States Wake Forest University Health Sciences Winston-Salem North Carolina
United States UMass Memorial Medical Center - University Campus Worcester Massachusetts

Sponsors (2)

Lead Sponsor Collaborator
Children's Oncology Group National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada,  Puerto Rico, 

Outcome

Type Measure Description Time frame Safety issue
Primary Disease Control Rate (Cohort I) 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. At 4 months
Primary Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I) 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. At 4 months
Primary Disease Control Rate (Cohort II) 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. At 12 months
Secondary Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab Sample means of trough concentrations of denosumab will be calculated. 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
Secondary Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab Sample medians of trough concentrations of denosumab will be calculated. 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
Secondary Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide Serum c-telopeptide in pg/ml Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7
Secondary Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio Urine n-telopeptide to creatinine ratio expressed as nMol BCE/mmol creatinine Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7
Secondary Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 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 Minimum of 2 years
Secondary Response Rate (CR or PR) for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances. Up to 3 years post-treatment
Secondary Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances. At 4 months
Secondary Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II) 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. At 12 months
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