Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma

Recurrent Osteosarcoma Clinical Trial

Official title:

Phase 2 Study of Denosumab (NSC# 744010), a RANK Ligand Antibody, for Recurrent or Refractory Osteosarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02470091
• Other study ID #: AOST1321
• Secondary ID: NCI-2015-00543s1
• Status: Completed
• Phase: Phase 2
• 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
• 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

Related Conditions & MeSH terms

• Metastatic Osteosarcoma
• Osteosarcoma
• Recurrence
• Recurrent Osteosarcoma
• Refractory Osteosarcoma
• Stage IV Osteosarcoma AJCC v7
• Stage IVA Osteosarcoma AJCC v7
• Stage IVB Osteosarcoma AJCC v7

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