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Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma

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ClinicalTrials.gov Identifier: NCT02470091
Recruitment Status : Active, not recruiting
First Posted : June 12, 2015
Last Update Posted : November 1, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This phase II trial studies how well denosumab works in treating patients with osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory). Monoclonal antibodies, such as denosumab, may block tumor growth in different ways by targeting certain cells.

Condition or disease Intervention/treatment Phase
Childhood Osteosarcoma Metastatic Osteosarcoma Recurrent Osteosarcoma Stage IV Osteosarcoma AJCC v7 Stage IVA Osteosarcoma AJCC v7 Stage IVB Osteosarcoma AJCC v7 Biological: Denosumab Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine whether denosumab therapy either increases the disease control rate at 4 months in patients with recurrent measurable osteosarcoma as compared to historical Children's Oncology Group (COG) experience or denosumab therapy produces an objective response rate greater than 5% (Cohort 1).

II. To determine whether denosumab therapy increases the disease control rate at 12 months in patients with recurrent resected osteosarcoma as compared to historical COG experience (Cohort 2).

SECONDARY OBJECTIVES:

I. To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab in subjects with recurrent osteosarcoma.

II. To describe the tolerability of denosumab in subjects with recurrent osteosarcoma.

III. To report the disease control rate and objective response rate for patients with recurrent osteosarcoma limited to bone.

IV. To investigate biological markers potentially associated with response to denosumab in patients with recurrent osteosarcoma.

OUTLINE:

Patients receive denosumab subcutaneously (SC) on day 1 (days 1, 8, and 15 of course 1 only). Treatment repeats every 4 weeks (28 days) for up to 24 months or 26 courses, whichever occurs first, in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for 1 year.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Denosumab (NSC# 744010), a RANK Ligand Antibody, for Recurrent or Refractory Osteosarcoma
Actual Study Start Date : November 9, 2015
Estimated Primary Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Denosumab

Arm Intervention/treatment
Experimental: Treatment (denosumab)
Patients receive denosumab SC on day 1 (days 1, 8, and 15 of course 1 only). Treatment repeats every 4 weeks (28 days) for up to 24 months or 26 courses, whichever occurs first, in the absence of disease progression or unacceptable toxicity.
Biological: Denosumab
Given SC
Other Names:
  • AMG 162
  • AMG-162
  • Prolia
  • Xgeva

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Disease control rate (Cohort I) [ Time Frame: At 4 months ]
    Compared to historical Children's Oncology Group (COG) experience or denosumab therapy produces an objective response rate greater than 5%.

  2. Response Evaluation Criteria in Solid Tumors (RECIST) response (complete response [CR] or partial response [PR] vs not CR or PR) (Cohort I) [ Time Frame: At 4 months ]
    Compared to historical COG experience or denosumab therapy produces an objective response rate greater than 5%.

  3. Disease control rate (Cohort II) [ Time Frame: At 12 months ]
    Compared to historical COG experience. Will estimate the relative hazard rate and 95% confidence interval associated with various categories using the proportional hazards regression model with the characteristic of interest as the only variable in the model. The logrank statistic will be used to quantify statistical significance.


Secondary Outcome Measures :
  1. Pharmacokinetic (PK) parameters of denosumab [ Time Frame: Days 1, 8, 15, and 22 of course 1, day 1 of courses 2-4 and 7, and days 1 and 15 of course 6 ]
    Sample means, medians and variances will be calculated. Clearance and volume of distribution will be determined.

  2. Pharmacodynamic (PD) parameters of denosumab [ Time Frame: Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7 ]
    Sample means, medians and variances will be calculated. Clearance and volume of distribution will be determined. PD will be characterized by urinary N-telopeptide normalized to urinary creatinine ratio and c-telopeptide levels. Both of these characteristics will be modeled according to a repeated measures linear regression model. Depending on the fit of the quadratic model, additional terms in powers of time since enrollment may be added to explore how the PD parameters vary with time.

  3. Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Minimum of 2 years ]
    Will use a Bayesian rule 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. Safety analyses will be performed in aggregate, by cohort, and by age group (=< 18 years and in patients > 18 years of age). The safety of denosumab in adults and adolescents will be compared.

  4. Response rate (CR or PR) for patients with recurrent osteosarcoma limited to bone (Cohort I) [ Time Frame: Up to 3 years post-treatment ]
    Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.

  5. Disease control rates for patients with recurrent osteosarcoma limited to bone (Cohort I) [ Time Frame: At 4 months ]
    Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.

  6. Disease control rates for patients with recurrent osteosarcoma limited to bone (Cohort II) [ Time Frame: At 12 months ]
    The proportion of patients who experience 12 month disease control 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.



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Ages Eligible for Study:   11 Years to 49 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Female patients must have a bone age of equal to or greater than 12 years of age as determined by local read of appropriate radiographic imaging
  • Male patients must have a bone age of equal to or greater than 14 years of age as determined by local read of appropriate radiographic imaging
  • Patients must have relapsed or become refractory to conventional therapy, with a regimen including some combination of high dose methotrexate, doxorubicin, cisplatin, ifosfamide and etoposide; and have had histologic verification of osteosarcoma at original diagnosis or at the time of recurrence
  • Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

    • Note: patients in Cohort 1 will be stratified as follows:

      • Stratum 1: Patients >= 11 years of age but < 18 years
      • Stratum 2: Patients >= 11 years of age but < 50 years
  • Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment

    • Patients will only be eligible after they have undergone complete surgical resection of suspected metastatic disease that is histopathologically confirmed to be osteosarcoma prior to enrollment

      • Note: the definition of complete resections is: gross resection of all disease as per the operating surgeon; post-operative imaging is not required for confirmation of complete resection
    • Patients must undergo resection of any lung lesion meeting criteria for likely metastatic disease, defined as:

      • 3 or more lesions > 5 mm in diameter OR a single lesion > 1 cm
    • Patients with lung as the only site of resected metastatic disease must have refused participation in protocol AOST1421

      • Note: this applies if AOST1421 is open to enrollment at the enrolling institution on the day the patient consents
  • 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
  • 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:

    • Age: 11 to < 13 years old; 1.2 (male, female) maximum serum creatinine (mg/dL)
    • Age: 13 to < 16 years old; 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL)
    • Age: >= 16 years old; 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x ULN for age
  • Serum calcium or albumin-adjusted serum calcium >= 2.0 mmol/L (8.0 mg/dL) and =< 2.9 mmol/L (11.5 mg/dL)

Exclusion Criteria:

  • Patients with known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium or vitamin D)
  • Patients who are receiving other cancer directed therapy at the time of enrollment
  • Patients who have previously received denosumab
  • Patients who have previously received mithramycin, strontium-89, samarium-153 or rhenium
  • Patients receiving bisphosphonates
  • Pre-existing conditions

    • Disorders associated with abnormal bone metabolism
    • Hypocalcemia that is not corrected with oral calcium supplementation
    • Vitamin D < 20 mg/mL
    • Paget?s disease
    • Prior history or current evidence of osteonecrosis of the jaw
    • Any dental or oral condition likely to result in disruption of mucosal integrity during denosumab therapy including: active dental or jaw condition requiring oral surgery or tooth extraction; non-healed dental or oral surgery or planned invasive dental procedures during the anticipated course of study therapy
    • Unstable systemic disease, excluding osteosarcoma, such as unstable proximal renal tubule dysfunction (Fanconi syndrome) or congestive heart failure
  • Pregnancy and breast feeding

    • Female patients who are pregnant; a pregnancy test is required for female patients of childbearing potential
    • Lactating females who plan to breastfeed their infants while on study therapy and through 5 months after completion of study therapy
    • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 5 months after the end of study treatment
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

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): NCT02470091


  Show 141 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Katherine Janeway Children's Oncology Group

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT02470091     History of Changes
Other Study ID Numbers: AOST1321
NCI-2015-00543 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
s15-01360
AOST1321
AOST1321 ( Other Identifier: Childrens Oncology Group )
AOST1321 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: June 12, 2015    Key Record Dates
Last Update Posted: November 1, 2018
Last Verified: July 2018

Additional relevant MeSH terms:
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs