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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 : August 5, 2021
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Metastatic Malignant Neoplasm in the Lung Metastatic Osteosarcoma Recurrent Osteosarcoma Biological: Dinutuximab Other: Laboratory Biomarker Analysis Other: Pharmacological Study Biological: Sargramostim Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: N/A
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
Actual Study Start Date : November 30, 2015
Actual Primary Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.


Other Outcome Measures:
  1. 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.

  2. KIR Genotype Analyses [ Time Frame: At enrollment ]
    KIR mismatch will be assessed from the pre-treatment blood specimen as present or absent.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 29 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02484443


Locations
Show Show 130 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Pooja Hingorani Children's Oncology Group
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02484443    
Other Study ID Numbers: 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 )
First Posted: June 29, 2015    Key Record Dates
Results First Posted: May 7, 2021
Last Update Posted: August 5, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Sarcoma
Dinutuximab
Sargramostim
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents