Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma
- Conditions
- Refractory OsteosarcomaMetastatic OsteosarcomaRecurrent OsteosarcomaStage IV Osteosarcoma AJCC v7Stage IVA Osteosarcoma AJCC v7Stage IVB Osteosarcoma AJCC v7
- Interventions
- Biological: DenosumabOther: Laboratory Biomarker AnalysisOther: Pharmacological Study
- Registration Number
- NCT02470091
- Lead Sponsor
- Children's Oncology Group
- 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.
- 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.
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 & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 56
-
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)
-
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
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment (denosumab) Pharmacological Study 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. Treatment (denosumab) 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. Treatment (denosumab) Laboratory Biomarker Analysis 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.
- Primary Outcome Measures
Name Time Method 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.
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.
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.
- Secondary Outcome Measures
Name Time Method 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.
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.
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
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
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
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.
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.
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.
Trial Locations
- Locations (141)
Children's Oncology Group
🇺🇸Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸Atlanta, Georgia, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
Kaiser Permanente Downey Medical Center
🇺🇸Downey, California, United States
UHHS-Chagrin Highlands Medical Center
🇺🇸Beachwood, Ohio, United States
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦Quebec, Canada
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Kaiser Permanente-Anaheim
🇺🇸Anaheim, California, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Crossroads Cancer Center
🇺🇸Effingham, Illinois, United States
Carle Physician Group-Mattoon/Charleston
🇺🇸Mattoon, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
The Carle Foundation Hospital
🇺🇸Urbana, Illinois, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸Indianapolis, Indiana, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Maine Children's Cancer Program
🇺🇸Scarborough, Maine, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
UMass Memorial Medical Center - University Campus
🇺🇸Worcester, Massachusetts, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸Las Vegas, Nevada, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Sunrise Hospital and Medical Center
🇺🇸Las Vegas, Nevada, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, 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-Bellflower
🇺🇸Bellflower, California, United States
Kaiser Permanente-Fontana
🇺🇸Fontana, California, 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
Kaiser Permanente-San Diego Zion
🇺🇸San Diego, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸Oakland, California, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Centralia Oncology Clinic
🇺🇸Centralia, Illinois, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
University of Illinois
🇺🇸Chicago, Illinois, United States
Carle at The Riverfront
🇺🇸Danville, Illinois, United States
Cancer Care Specialists of Illinois - Decatur
🇺🇸Decatur, Illinois, United States
Carle Physician Group-Effingham
🇺🇸Effingham, Illinois, United States
Cancer Care Center of O'Fallon
🇺🇸O'Fallon, Illinois, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Albany Medical Center
🇺🇸Albany, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Children's Hospital Medical Center of Akron
🇺🇸Akron, Ohio, United States
Case Western Reserve University
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Penn State Children's Hospital
🇺🇸Hershey, Pennsylvania, 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
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
University of Virginia Cancer Center
🇺🇸Charlottesville, Virginia, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Ascension Saint John Hospital
🇺🇸Detroit, Michigan, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸Denver, Colorado, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Saint Luke's Cancer Institute - Boise
🇺🇸Boise, Idaho, United States
Saint Mary's Hospital
🇺🇸West Palm Beach, Florida, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Saint Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
West Virginia University Healthcare
🇺🇸Morgantown, West Virginia, United States
Children's Hospital
🇨🇦London, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦Montreal, Quebec, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸Grand Rapids, Michigan, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
San Jorge Children's Hospital
🇵🇷San Juan, Puerto Rico
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
University Pediatric Hospital
🇵🇷San Juan, Puerto Rico
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, 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 Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸Orlando, Florida, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Ochsner Medical Center Jefferson
🇺🇸New Orleans, Louisiana, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States