Metastatic Malignant Neoplasm in the Lung, Metastatic Osteosarcoma, Recurrent Osteosarcoma
Conditions
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.
Interventions
BIOLOGICALDinutuximab
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
BIOLOGICALSargramostim
Given SC
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 29 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| HACA Titer | At enrollment, at the start of each cycle of therapy and within 30 days of the end of cycle 5 | HACA titer will be determined in each blood sample provided to the HACA reference laboratory. |
| Tumor GD2 Expression | At study enrollment | Archival tumor tissue will be assessed by immunohistochemistry to provide the level of GD2 expression in tissue as an integer between 0 and 3 with 0 indicating no GD2 expression and 3 indicating strong GD2 expression. |
| Circulating Tumor Deoxyribonucleic Acid Detection | 5 cycles of protocol therapy planned as 140 days | Statistical considerations for specific future studies will be provided. |
| KIR Genotype Analyses | At enrollment | KIR mismatch will be assessed from the pre-treatment blood specimen as present or absent. |
| NKp30c Genotype Analyses | At enrollment | Status of the immunosuppressive isoform of NKp30c KIR mismatch will be assessed from the pre-treatment blood specimen as present or absent. |
| FcgammaR Genotype Analyses | At enrollment | FcgammaR genotype will be assessed from the pre-treatment blood specimen as H/R, R/R or H/H. |
| Change in Circulating Ligand B7-H6 Levels | Cycle 1 of therapy planned to be 21 days | The change in surface expression of ligand B7-H6 in terms of counts between the blood sample taken prior to the start of protocol therapy and the end of cycle 1 will be calculated. Patients who do not receive all prescribed protocol therapy during cycle 1 will not be evaluable for this outcome measure. |
| Banking of Tumor Samples (Optional) | 5 cycles of protocol therapy planned as 140 days | Individual statistical plans will be developed for future studies answering a specific question using these banked tumor specimens. |
Countries
Australia, Canada, New Zealand, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Sargramostim and 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. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 2 |
| Overall Study | Lack of Efficacy | 28 |
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Treatment (Sargramostim and Dinutuximab) |
|---|---|
| Age, Categorical <=18 years | 33 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 15 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment Australia | 2 participants |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment New Zealand | 1 participants |
| Region of Enrollment United States | 37 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 39 |
| other Total, other adverse events | 28 / 39 |
| serious Total, serious adverse events | 12 / 39 |
Outcome results
Primary
Disease Control
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.
Time frame: 12 months after study enrollment
Population: All eligible patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Sargramostim and Dinutuximab) | Disease Control | 11 Participants |
Secondary
Area Under the Curve (AUC)0 to Infinity of Serum Dinutuximab
(AUC)0 to infinity of serum dinutuximab in mg-h/L.
Time frame: 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
Population: Analysis population includes only patients for whom blood samples were submitted for pharmacokinetic analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Sargramostim and Dinutuximab) | Area Under the Curve (AUC)0 to Infinity of Serum Dinutuximab | 2136 mg-h/L |
Secondary
Maximum of Concentration (Cmax) of the Serum Concentration Dinutuximab
Cmax of the serum concentration dinutuximab as mg/L.
Time frame: 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
Population: Analysis population includes only patients for whom blood samples were submitted for pharmacokinetic analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Sargramostim and Dinutuximab) | Maximum of Concentration (Cmax) of the Serum Concentration Dinutuximab | 18.4 mg/L |
Secondary
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
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.
Time frame: 5 cycles of protocol therapy planned as 140 days
Population: 39 patients were treated on protocol therapy. One hundred thirty-six cycles were reported for the analysis of dose limiting toxicity
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Sargramostim and Dinutuximab) | 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 | 1 cycles |
Secondary
T 1/2 Alpha of the Serum Concentration of Dinutuximab
T 1/2 alpha of the serum concentration of dinutuximab in days
Time frame: 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
Population: Analysis population includes only patients for whom blood samples were submitted for pharmacokinetic analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Sargramostim and Dinutuximab) | T 1/2 Alpha of the Serum Concentration of Dinutuximab | 0.8 days |
Secondary
T 1/2 Beta of the Serum Concentration of Dinutuximab
T 1/2 beta of the serum concentration of dinutuximab in days
Time frame: 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
Population: Analysis population includes only patients for whom blood samples were submitted for pharmacokinetic analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Sargramostim and Dinutuximab) | T 1/2 Beta of the Serum Concentration of Dinutuximab | 7.5 days |
Other Pre-specified
Banking of Tumor Samples (Optional)
Individual statistical plans will be developed for future studies answering a specific question using these banked tumor specimens.
Time frame: 5 cycles of protocol therapy planned as 140 days
Other Pre-specified
Change in Circulating Ligand B7-H6 Levels
The change in surface expression of ligand B7-H6 in terms of counts between the blood sample taken prior to the start of protocol therapy and the end of cycle 1 will be calculated. Patients who do not receive all prescribed protocol therapy during cycle 1 will not be evaluable for this outcome measure.
Time frame: Cycle 1 of therapy planned to be 21 days
Other Pre-specified
Circulating Tumor Deoxyribonucleic Acid Detection
Statistical considerations for specific future studies will be provided.
Time frame: 5 cycles of protocol therapy planned as 140 days
Other Pre-specified
FcgammaR Genotype Analyses
FcgammaR genotype will be assessed from the pre-treatment blood specimen as H/R, R/R or H/H.
Time frame: At enrollment
Other Pre-specified
HACA Titer
HACA titer will be determined in each blood sample provided to the HACA reference laboratory.
Time frame: At enrollment, at the start of each cycle of therapy and within 30 days of the end of cycle 5
Other Pre-specified
KIR Genotype Analyses
KIR mismatch will be assessed from the pre-treatment blood specimen as present or absent.
Time frame: At enrollment
Other Pre-specified
NKp30c Genotype Analyses
Status of the immunosuppressive isoform of NKp30c KIR mismatch will be assessed from the pre-treatment blood specimen as present or absent.
Time frame: At enrollment
Other Pre-specified
Tumor GD2 Expression
Archival tumor tissue will be assessed by immunohistochemistry to provide the level of GD2 expression in tissue as an integer between 0 and 3 with 0 indicating no GD2 expression and 3 indicating strong GD2 expression.
Time frame: At study enrollment