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Dinutuximab in Combination With Sargramostim in Treating Patients With Recurrent Osteosarcoma

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ClinicalTrials.gov Identifier: NCT02484443
Recruitment Status : Active, not recruiting
First Posted : June 29, 2015
Results First Posted : May 7, 2021
Last Update Posted : October 21, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE June 26, 2015
First Posted Date  ICMJE June 29, 2015
Results First Submitted Date  ICMJE April 12, 2021
Results First Posted Date  ICMJE May 7, 2021
Last Update Posted Date October 21, 2021
Actual Study Start Date  ICMJE November 30, 2015
Actual Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2021)
Disease Control [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 26, 2015)
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 27, 2021)
  • T 1/2 Alpha of the Serum Concentration of Dinutuximab [ 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 ]
    T 1/2 alpha of the serum concentration of dinutuximab in days
  • T 1/2 Beta of the Serum Concentration of Dinutuximab [ 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 ]
    T 1/2 beta of the serum concentration of dinutuximab in days
  • Maximum of Concentration (Cmax) of the Serum Concentration Dinutuximab [ 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 ]
    Cmax of the serum concentration dinutuximab as mg/L.
  • Area Under the Curve (AUC)0 to Infinity of Serum Dinutuximab [ 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 ]
    (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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2015)
  • Incidence of UT, 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: On days 4 and 5 of course 1 and then prior to the start of course 2 ]
    The average and standard deviation of estimates will be reported.
Current Other Pre-specified Outcome Measures
 (submitted: April 12, 2021)
  • Tumor GD2 Expression [ Time Frame: 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.
  • KIR Genotype Analyses [ Time Frame: At enrollment ]
    KIR mismatch will be assessed from the pre-treatment blood specimen as present or absent.
  • NKp30c Genotype Analyses [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.
  • HACA Titer [ Time Frame: 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.
  • Circulating Tumor Deoxyribonucleic Acid Detection [ Time Frame: 5 cycles of protocol therapy planned as 140 days ]
    Statistical considerations for specific future studies will be provided.
Original Other Pre-specified Outcome Measures
 (submitted: June 26, 2015)
  • 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 to up to the end of course 1 ]
    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.
  • KIR, NKp30, and FcgammaR genotype analyses [ Time Frame: Up to 4 years ]
    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 (ELIZA) 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 ELIZA 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.
 
Descriptive Information
Brief Title  ICMJE Dinutuximab in Combination With Sargramostim in Treating Patients With Recurrent Osteosarcoma
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Malignant Neoplasm in the Lung
  • Metastatic Osteosarcoma
  • Recurrent Osteosarcoma
Intervention  ICMJE
  • Biological: Dinutuximab
    Given IV
    Other Names:
    • Ch 14.18UTC
    • Ch14.18
    • MOAB Ch14.18
    • monoclonal antibody Ch14.18
    • Unituxin
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Biological: Sargramostim
    Given SC
    Other Names:
    • 23-L-Leucinecolony-Stimulating Factor 2
    • DRG-0012
    • Leukine
    • Prokine
    • rhu GM-CFS
    • Sagramostim
    • Sargramostatin
Study Arms  ICMJE 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.
Interventions:
  • Biological: Dinutuximab
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Biological: Sargramostim
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 3, 2020)
41
Original Estimated Enrollment  ICMJE
 (submitted: June 26, 2015)
39
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 29 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02484443
Other Study ID Numbers  ICMJE NCI-2015-01001
NCI-2015-01001 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AOST1421
s16-00451
AOST1421 ( Other Identifier: Children's Oncology Group )
AOST1421 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Pooja Hingorani Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP