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Dinutuximab in Combination With Sargramostim in Treating Patients With Recurrent Osteosarcoma

This study has suspended participant recruitment.
(Other - Evaluation of 2 SAEs)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02484443
First received: June 26, 2015
Last updated: July 17, 2017
Last verified: May 2017
  Purpose
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 Intervention Phase
Metastatic Malignant Neoplasm in the Lung Metastatic Osteosarcoma Recurrent Osteosarcoma Biological: Dinutuximab Other: Laboratory Biomarker Analysis Other: Pharmacological Study Biological: Sargramostim Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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: 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.


Other Outcome Measures:
  • 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 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.

  • ctDNA 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 (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.


Estimated Enrollment: 44
Actual Study Start Date: November 30, 2015
Estimated Primary Completion Date: December 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (sargramostim and dinutuximab)
Patients receive sargramostim SC on days 1-14 and dinutuximab IV over 20 hours on days 4 and 5 (dinutuximab infusion may be extended for an additional 2 days 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

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 in the proposed administration schedule.

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

TERTIARY OBJECTIVES:

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

II. To assess killer cell immunoglobulin-like receptor (KIR) and Fcgamma receptor (FcgammaR) genotypes, natural killer cell p30 (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) on days 1-14 and dinutuximab intravenously (IV) over 20 hours on days 4 and 5 (dinutuximab infusion may be extended for an additional 2 days 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.

  Eligibility

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 (Neulasta) 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
  • 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%
  • Patients with a known seizure disorder may be enrolled if on anticonvulsants and/or well controlled
  • 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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02484443

  Show 119 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Pooja Hingorani Children's Oncology Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02484443     History of Changes
Other Study ID Numbers: NCI-2015-01001
NCI-2015-01001 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AOST1421
AOST1421 ( Other Identifier: Childrens Oncology Group )
AOST1421 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Study First Received: June 26, 2015
Last Updated: July 17, 2017

Additional relevant MeSH terms:
Neoplasms
Osteosarcoma
Neoplasms, Second Primary
Lung Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Sarcoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Antibodies
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 21, 2017