Dinutuximab in Combination With Sargramostim in Treating Patients With Recurrent Osteosarcoma
|Metastatic Malignant Neoplasm in the Lung Metastatic Osteosarcoma Recurrent Osteosarcoma||Biological: Dinutuximab Other: Laboratory Biomarker Analysis Other: Pharmacological Study Biological: Sargramostim||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase 2 Study of Human-Mouse Chimeric Anti-disialoganglioside Monoclonal Antibody ch14.18 (Dinutuximab, NSC# 764038) in Combination With Sargramostim (GM-CSF) in Patients With Recurrent Osteosarcoma|
- Disease control [ Time Frame: During the first 12 months ]The probability of remaining event-free as a function of time since enrollment will be estimated by the method of Kaplan and Meier. The complementary log-log transformation of the Kaplan-Meier estimate of the 12 month disease control probability will be used to construct confidence intervals of that probability. Only patients who can be confirmed to be free of detectable disease 12 months after enrollment, without intervening disease progression, will be considered to have experienced 12 month disease control.
- Incidence of unacceptable toxicity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 4 years ]A Bayesian rule will be used to monitor for excessive toxicity. Descriptive analyses of this safety information will be performed and will include the incidence of adverse events, severe adverse events, serious adverse events, and fatal adverse events. Type, frequency, and severity of laboratory abnormalities will also be analyzed.
- Pharmacokinetics of dinutuximab [ Time Frame: Baseline, 4 hours, and immediately before end of dinutuximab infusion on day 4, 4 hours before, immediately before, 4-8 hours, and 4-10 days following dinutuximab infusion on day 5 of course 1, and then prior to the start of course 2 ]The average and standard deviation of estimates will be reported.
- Banking of tumor samples (optional) [ Time Frame: During first 12 months from enrollment ]Individual statistical plans will be developed for future studies answering a specific question using these banked tumor specimens.
- Change in circulating ligand B7-H6 levels [ Time Frame: Baseline up to 4 years ]Additionally, serum for the evaluation of ligand levels at relapse will be requested. The change will be estimated by the average intra-patient change and the variance will be estimated by the variance of the intra-patient differences.
- Circulating tumor deoxyribonucleic acid detection [ Time Frame: Up to 4 years ]Statistical considerations for specific future studies will be provided.
- KIR, NKp30, and FcgammaR genotype analyses [ Time Frame: Baseline ]The outcome measure will be DC success (yes versus no). Logistic regression using the categorical FcgammaR result will be fitted to the data. The fitted coefficients from the logistic regression, and the p-value for the test of the hypothesis of no relationship between FcgammaR result and probability of DC success will be used to characterize this exploratory analysis. Logistic regression using the categorical KIR/KIR ligand mismatch (present v. absent) will be fitted to the data.
- Profile of HACA during immunotherapy [ Time Frame: Up to 30 days post-treatment ]At each time point, the optical density of the enzyme-linked immunosorbent assay (ELISA) bridging assay will be calculated. The number of patients who are HACA positive divided by the number of patients with a successful HACA assay at each time point will be used to quantify the fraction of patients displaying HACA activity. Will also graph the average optical density of the ELISA assay over all patients at each time point.
- Tumor GD2 expression [ Time Frame: Up to 4 weeks post-treatment ]The relationship between probability of disease control (DC) and tumor GD2 expression will be assessed. The outcome measure will be DC success (yes versus no). Logistic regression using the categorical immunohistochemistry (IHC) result will be fitted to the data. The fitted coefficients from the logistic regression, and the p-value for the test of the hypothesis of no relationship between IHC result and probability of DC success will be used to characterize this exploratory analysis. Trend will also be assessed using the actual IHC numerical value.
|Actual Study Start Date:||November 30, 2015|
|Estimated Study Completion Date:||December 31, 2018|
|Estimated Primary Completion Date:||December 31, 2018 (Final data collection date for primary outcome measure)|
Experimental: 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.
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesOther: Pharmacological Study
Correlative studiesBiological: Sargramostim
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.
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.
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02484443
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|Principal Investigator:||Pooja Hingorani||Children's Oncology Group|