Dinutuximab in Combination With Sargramostim in Treating Patients With Recurrent Osteosarcoma

Phase 2

Completed

Conditions: Metastatic Osteosarcoma
Recurrent Osteosarcoma
Metastatic Malignant Neoplasm in the Lung

Interventions: Biological: Dinutuximab
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Biological: Sargramostim

Registration Number: NCT02484443

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies how well dinutuximab works when given with sargramostim in treating patients with osteosarcoma that has come back after treatment (recurrent). Monoclonal antibodies, such as dinutuximab, may find tumor cells and help kill them. Sargramostim may help the body increase the amount of white blood cells it produces, which help the body fight off infections. Giving dinutuximab with sargramostim may work better and kill more cancer cells.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the disease control rate in patients with completely resected recurrent osteosarcoma treated with ch14.18 (dinutuximab) in combination with sargramostim (granulocyte-macrophage colony-stimulating factor \[GM-CSF\]) as compared to historical Children's Oncology Group (COG) experience.

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetics of ch14.18 (dinutuximab) in patients with recurrent osteosarcoma.

II. To determine the occurrence of unacceptable toxicity (UT) in patients with recurrent osteosarcoma treated with ch14.18 (dinutuximab) in combination with sargramostim.

III. To assess the relationship between probability of disease control and tumor ganglioside GD2 (GD2) expression.

TERTIARY OBJECTIVES:

I. To assess the relationship between probability of disease control and tumor GD2 expression.

II. To assess KIR and Fcgamma receptor (FcgammaR) genotypes, NKp30 isoforms and its circulating ligand, B7-H6, and their relationships to the probability of disease control.

III. To attempt banking of tumor samples for future research studies from patients enrolled on study who undergo biopsy or resection of suspected metastatic disease recurrence while on protocol therapy or during the evaluation period.

IV. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy.

V. To bank serial plasma samples for future studies of circulating tumor deoxyribonucleic acid (ctDNA) detection as a marker of disease progression and response.

OUTLINE:

Patients receive sargramostim subcutaneously (SC) once daily (QD) on days 1-14 and dinutuximab intravenously (IV) over 10 hours on days 4-7 (dinutuximab infusion may be extended up to a total of 20 hours per day for anticipated toxicities). Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 8 and 12 months.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 41

Inclusion Criteria

Patients must have histologic diagnosis of osteosarcoma at original diagnosis
Patients must have had at least one episode of disease recurrence in the lungs without limitation on number of episodes of recurrence as long as they meet the following criteria:
- Surgical resection of all possible sites of suspected pulmonary metastases in order to achieve a complete remission within 4 weeks prior to study enrollment**
- Pathologic confirmation of metastases from at least one of the resected sites
  - For patients with bilateral pulmonary metastases, resection must be performed from both lungs and the study enrollment must be within 4 weeks from date of the last lung surgery
- Note: If surgery related changes such as atelectasis are seen on the post-operative computed tomography (CT) scan, patients will remain eligible to enroll as long as the operating surgeon believes that all sites of metastases were resected; patients with positive microscopic margins will be eligible to enroll
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
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
- Myelosuppressive anti-cancer therapy: must not have been received within 2 weeks of study entry (4 weeks if prior nitrosourea)
- Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent
- Radiation therapy (RT): >= 2 weeks for local palliative radiation therapy (RT) (small port); >= 6 weeks must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation
- Surgery: >= 2 weeks from last major surgery, including pulmonary metastasectomy, with the exclusion of a central line placement and core needle or small open biopsies
Patient must not have received pegfilgrastim within 14 days of enrollment
Patient must not have received filgrastim (G-CSF, Neupogen) within 7 days of enrollment
Patient must not have received immune suppressants: corticosteroids (for other than allergic reactions and anaphylaxis), cyclosporine or tacrolimus within 7 days of enrollment
- Note: the use of topical and/or inhalational steroids is allowed
Total absolute phagocyte count (APC = [%neutrophils + %monocytes) x white blood cells [WBC]) is at least 1000/uL
Platelet count >= 50,000/uL
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:
- 1 month to < 6 months: 0.4 (male) 0.4 (female)
- 6 months to < 1 year: 0.5 (male), 0.5 (female)
- 1 to < 2 years: 0.6 (male), 0.6 (female)
- 2 to < 6 years: 0.8 (male), 0.8 (female)
- 6 to < 10 years: 1 (male), 1 (female)
- 10 to < 13 years: 1.2 (male), 1.2 (female)
- 13 to < 16 years: 1.5 (male), 1.4 (female)
- >= 16 years: 1.7 (male), 1.4 (female)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)
Serum albumin >= 2 g/dL
Baseline electrocardiogram (EKG) shows normal corrected QT interval (QTc) interval of =< 470 milliseconds (ms)
Shortening fraction of >= 27% by echocardiogram, or
Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
No evidence of dyspnea at rest, no history of exercise intolerance, and a pulse oximetry > 94%
Patient has no known history of seizure disorder
Central nervous system (CNS) toxicity including peripheral neuropathy =< grade 2

Exclusion Criteria

Patients with distant bone metastases at original diagnosis or relapse (patients with only skip lesions will be eligible)
Patients with concurrent local and pulmonary recurrence at the time of enrollment; note: patients who had local recurrence previously that has been treated and now present with an isolated pulmonary recurrence and meet the surgical resection criteria stated above will be eligible
Patients with primary refractory disease with progression of the primary tumor on initial therapy
Patients with CNS disease or other sites of extra-pulmonary metastases at the time of most recent episode of disease recurrence preceding enrollment
Patients with a prior hypersensitivity reaction to sargramostim
Patients who have received prior anti-GD2 therapy, including chimeric antigen receptor (CAR) T cells directed against GD2 antigen
Female patients who are pregnant are ineligible
Lactating females are not eligible unless they have agreed not to breastfeed their infants
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation; patients should maintain adequate contraception for a minimum of 2 months after the last dose of ch14.18 (dinutuximab)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (sargramostim and dinutuximab)	Pharmacological Study	Patients receive sargramostim SC QD on days 1-14 and dinutuximab IV over 10 hours on days 4-7 (dinutuximab infusion may be extended up to a total of 20 hours per day for anticipated toxicities). Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.
Treatment (sargramostim and dinutuximab)	Laboratory Biomarker Analysis	Patients receive sargramostim SC QD on days 1-14 and dinutuximab IV over 10 hours on days 4-7 (dinutuximab infusion may be extended up to a total of 20 hours per day for anticipated toxicities). Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.
Treatment (sargramostim and dinutuximab)	Dinutuximab	Patients receive sargramostim SC QD on days 1-14 and dinutuximab IV over 10 hours on days 4-7 (dinutuximab infusion may be extended up to a total of 20 hours per day for anticipated toxicities). Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.
Treatment (sargramostim and dinutuximab)	Sargramostim	Patients receive sargramostim SC QD on days 1-14 and dinutuximab IV over 10 hours on days 4-7 (dinutuximab infusion may be extended up to a total of 20 hours per day for anticipated toxicities). Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Disease Control	12 months after study enrollment	Patients who can be confirmed to be free of detectable disease 12 months after enrollment, without intervening disease progression, will be considered to have demonstrated 12 month disease control. All other eligible patients will be considered not to have demonstrated 12 month disease control.

Secondary Outcome Measures

Name	Time	Method
T 1/2 Beta of the Serum Concentration of Dinutuximab	Cycle 1 Day 4 and Day 7: pre-infusion, hour 4-6, end of infusion, 4-8 hours post infusion. Once between days 11-17. Cycle 2 Day 0 or 1	T 1/2 beta of the serum concentration of dinutuximab in days
Number of Cycles Where an Unacceptable Toxicity as Defined in the Protocol Using The National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 Was Observed	5 cycles of protocol therapy planned as 140 days	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. Occurrence of unacceptable toxicity as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, coded as present or absent, in each cycle received by eligible patients where all prescribed therapy for the cycle is received or the patient experiences unacceptable toxicity.
Maximum of Concentration (Cmax) of the Serum Concentration Dinutuximab	Cycle 1 Day 4 and Day 7: pre-infusion, hour 4-6, end of infusion, 4-8 hours post infusion. Once between days 11-17. Cycle 2 Day 0 or 1	Cmax of the serum concentration dinutuximab as mg/L.
T 1/2 Alpha of the Serum Concentration of Dinutuximab	Cycle 1 Day 4 and Day 7: pre-infusion, hour 4-6, end of infusion, 4-8 hours post infusion. Once between days 11-17. Cycle 2 Day 0 or 1	T 1/2 alpha of the serum concentration of dinutuximab in days
Area Under the Curve (AUC)0 to Infinity of Serum Dinutuximab	Cycle 1 Day 4 and Day 7: pre-infusion, hour 4-6, end of infusion, 4-8 hours post infusion. Once between days 11-17. Cycle 2 Day 0 or 1	(AUC)0 to infinity of serum dinutuximab in mg-h/L.

Trial Locations

Locations (130): Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸
Oakland, California, United States
Saint Luke's Cancer Institute - Boise
🇺🇸
Boise, Idaho, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
Covenant Children's Hospital
🇺🇸
Lubbock, Texas, United States
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
John Hunter Children's Hospital
🇦🇺
Hunter Regional Mail Centre, New South Wales, Australia
Cardinal Glennon Children's Medical Center
🇺🇸
Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
Albany Medical Center
🇺🇸
Albany, New York, United States
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Alberta Children's Hospital
🇨🇦
Calgary, Alberta, Canada
Christchurch Hospital
🇳🇿
Christchurch, New Zealand
Starship Children's Hospital
🇳🇿
Grafton, Auckland, New Zealand
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
University Medical Center of Southern Nevada
🇺🇸
Las Vegas, Nevada, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸
Las Vegas, Nevada, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Nicklaus Children's Hospital
🇺🇸
Miami, Florida, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸
Indianapolis, Indiana, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Saint Mary's Hospital
🇺🇸
West Palm Beach, Florida, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸
Toledo, Ohio, United States
Saint Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Children's Hospital of The King's Daughters
🇺🇸
Norfolk, Virginia, United States
Madigan Army Medical Center
🇺🇸
Tacoma, Washington, United States
Sydney Children's Hospital
🇦🇺
Randwick, New South Wales, Australia
Women's and Children's Hospital-Adelaide
🇦🇺
North Adelaide, South Australia, Australia
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, 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
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Sanford Broadway Medical Center
🇺🇸
Fargo, North Dakota, United States
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
University of Rochester
🇺🇸
Rochester, New York, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Ascension Saint John Hospital
🇺🇸
Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
The Children's Hospital at TriStar Centennial
🇺🇸
Nashville, Tennessee, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Beaumont Children's Hospital-Royal Oak
🇺🇸
Royal Oak, Michigan, United States
Sunrise Hospital and Medical Center
🇺🇸
Las Vegas, Nevada, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸
Grand Rapids, Michigan, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Monash Medical Center-Clayton Campus
🇦🇺
Clayton, Victoria, Australia
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸
Lebanon, New Hampshire, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Summerlin Hospital Medical Center
🇺🇸
Las Vegas, Nevada, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
University Pediatric Hospital
🇵🇷
San Juan, Puerto Rico
Royal Children's Hospital
🇦🇺
Parkville, Victoria, Australia
West Virginia University Healthcare
🇺🇸
Morgantown, West Virginia, United States
University of Vermont and State Agricultural College
🇺🇸
Burlington, Vermont, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦
Quebec, Canada
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
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Nemours Children's Hospital
🇺🇸
Orlando, Florida, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Ochsner Medical Center Jefferson
🇺🇸
New Orleans, Louisiana, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Arnold Palmer Hospital for Children
🇺🇸
Orlando, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸
Gainesville, Florida, United States
Kapiolani Medical Center for Women and Children
🇺🇸
Honolulu, Hawaii, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Children's Hospital
🇨🇦
London, Ontario, Canada
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Queensland Children's Hospital
🇦🇺
South Brisbane, Queensland, Australia