Metastatic Osteosarcoma, Recurrent Osteosarcoma, Refractory Osteosarcoma, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7, Stage IV Osteosarcoma AJCC v7
Conditions
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). Immunotherapy with monoclonal antibodies, such as denosumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
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.
Interventions
BIOLOGICALDenosumab
Given SC
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
11 Years to 49 Years
Healthy volunteers
No
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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (Cohort I) | At 4 months | Disease control interval was calculated as the time from enrolment until detection of new disease or progression of an existing site of disease as determined by the treating physician. Disease control interval of at least 4 months was considered disease control success. |
| Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I) | At 4 months | Per Response Evaluation Criteria In Solid TumorsCriteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response(CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Disease Control Rate (Cohort II) | At 12 months | Disease control interval was calculated as the time from enrolment until detection of new disease as determined by the treating physician. Disease control interval of at least 12 months was considered disease control success. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7 | Urine n-telopeptide to creatinine ratio expressed as nMol BCE/mmol creatinine |
| Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Minimum of 2 years | 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 |
| Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | 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 of trough concentrations of denosumab will be calculated. |
| Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) | At 4 months | Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances. |
| Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II) | At 12 months | Disease control interval was calculated at the time from enrolment until detection of new disease as determined by the treating physician. The proportion of patients who experience disease control of at least 12 months will be estimated by the method of Kaplan and Meier. |
| Response Rate (CR or PR) for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) | 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. |
| Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | 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 medians of trough concentrations of denosumab will be calculated. |
| Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7 | Serum c-telopeptide in pg/ml |
Countries
Canada, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Measurable Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | 16 |
| Cohort 2: Resection Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment | 40 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: Measurable | Cohort 2: Resection | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 26 Participants | 42 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 14 Participants | 14 Participants |
| Age, Continuous | 15 years | 17 years | 16 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 32 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) White | 10 Participants | 32 Participants | 42 Participants |
| Region of Enrollment Canada | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 16 participants | 39 participants | 55 participants |
| Sex: Female, Male Female | 5 Participants | 17 Participants | 22 Participants |
| Sex: Female, Male Male | 11 Participants | 23 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 15 | 20 / 38 |
| other Total, other adverse events | 1 / 15 | 8 / 38 |
| serious Total, serious adverse events | 6 / 15 | 4 / 38 |
Outcome results
Primary
Disease Control Rate (Cohort I)
Disease control interval was calculated as the time from enrolment until detection of new disease or progression of an existing site of disease as determined by the treating physician. Disease control interval of at least 4 months was considered disease control success.
Time frame: At 4 months
Population: 1 patient was excluded due to withdrawal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Measurable | Disease Control Rate (Cohort I) | 1 participants |
Primary
Disease Control Rate (Cohort II)
Disease control interval was calculated as the time from enrolment until detection of new disease as determined by the treating physician. Disease control interval of at least 12 months was considered disease control success.
Time frame: At 12 months
Population: 2 patients were excluded due to ineligibility
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Measurable | Disease Control Rate (Cohort II) | 10 participants |
Primary
Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I)
Per Response Evaluation Criteria In Solid TumorsCriteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response(CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: At 4 months
Population: 1 patient was excluded due to withdrawal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Measurable | Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I) | 0 participants |
Secondary
Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I)
Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.
Time frame: At 4 months
Population: There were not any patients that met criteria for bone site
Secondary
Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II)
Disease control interval was calculated at the time from enrolment until detection of new disease as determined by the treating physician. The proportion of patients who experience disease control of at least 12 months will be estimated by the method of Kaplan and Meier.
Time frame: At 12 months
Population: Patients that met criteria for bone site
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Measurable | Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II) | 0.667 proportion of patients |
Secondary
Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
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
Time frame: Minimum of 2 years
Population: 56 patients were treated on protocol therapy. Three hundred seventy-three cycles were reported for the analysis of dose limiting toxicity
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Measurable | Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | 1 cycles |
Secondary
Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide
Serum c-telopeptide in pg/ml
Time frame: Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7
Population: All eligible participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 1 | 1713 pg/ml | Standard Deviation 1857 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 8 | 220.5 pg/ml | Standard Deviation 77 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 15 | 203.1818 pg/ml | Standard Deviation 68 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 22 | 210.8889 pg/ml | Standard Deviation 95 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 2, Day 1 | 200.8 pg/ml | Standard Deviation 78 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 3, Day 1 | 115 pg/ml | — |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 4, Day 1 | 116 pg/ml | — |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 7, Day 1 | 108 pg/ml | — |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 7, Day 1 | 168.9 pg/ml | Standard Deviation 81 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 1 | 944.5 pg/ml | Standard Deviation 543 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 2, Day 1 | 152.2032 pg/ml | Standard Deviation 61 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 8 | 244.0625 pg/ml | Standard Deviation 259 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 4, Day 1 | 137.0235 pg/ml | Standard Deviation 80 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 15 | 171.24 pg/ml | Standard Deviation 86 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 3, Day 1 | 147.8818 pg/ml | Standard Deviation 85 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide | Serum c-telopeptide (pg/ml): Cycle 1, Day 22 | 178.5033 pg/ml | Standard Deviation 96 |
Secondary
Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio
Urine n-telopeptide to creatinine ratio expressed as nMol BCE/mmol creatinine
Time frame: Days 1, 8, 15, and 22 of course 1 and day 1 of courses 2-4 and 7
Population: All eligible participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 1 | 322.2 nMol BCE/mmol creatinine | Standard Deviation 307 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 8 | 30.36364 nMol BCE/mmol creatinine | Standard Deviation 20 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 15 | 26.18182 nMol BCE/mmol creatinine | Standard Deviation 14 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 22 | 26.55556 nMol BCE/mmol creatinine | Standard Deviation 19 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 2, Day 1 | 22.1 nMol BCE/mmol creatinine | Standard Deviation 15 |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 3, Day 1 | 14 nMol BCE/mmol creatinine | — |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 4, Day 1 | 20 nMol BCE/mmol creatinine | — |
| Cohort 1: Measurable | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 7, Day 1 | 13 nMol BCE/mmol creatinine | — |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 7, Day 1 | 22.4 nMol BCE/mmol creatinine | Standard Deviation 18 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 1 | 190.7714 nMol BCE/mmol creatinine | Standard Deviation 283 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 2, Day 1 | 28.42857 nMol BCE/mmol creatinine | Standard Deviation 45 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 8 | 34.1875 nMol BCE/mmol creatinine | Standard Deviation 35 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 4, Day 1 | 29.29412 nMol BCE/mmol creatinine | Standard Deviation 31 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 15 | 32.3 nMol BCE/mmol creatinine | Standard Deviation 36 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 3, Day 1 | 24.7619 nMol BCE/mmol creatinine | Standard Deviation 20 |
| Cohort 2: Resection | Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio | Urine n-telopeptide to creatinine ratio (nMol BCE/mmol creatinine): Cycle 1, Day 22 | 32.16129 nMol BCE/mmol creatinine | Standard Deviation 40 |
Secondary
Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab
Sample means of trough concentrations of denosumab will be calculated.
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
Population: The number of patients who contributed samples varied across cycles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 3, Day 1 | 23.8 ng/ml | — |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 22 | 31.8 ng/ml | Standard Deviation 12.85573802 |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 4, Day 1 | 23.7 ng/ml | — |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 15 | 20.57 ng/ml | Standard Deviation 8.290958931 |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 1 | 20.3 ng/ml | — |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 2, Day 1 | 30.57 ng/ml | Standard Deviation 10.78239306 |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 15 | 23.2 ng/ml | — |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 8 | 11.59 ng/ml | Standard Deviation 3.836665219 |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 1 | 0 ng/ml | Standard Deviation 0 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 15 | 26.66 ng/ml | Standard Deviation 11.95742447 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 7, Day 1 | 30.22 ng/ml | Standard Deviation 13.89748179 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 1 | 0 ng/ml | Standard Deviation 0 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 8 | 10.81 ng/ml | Standard Deviation 4.514421336 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 15 | 22.07 ng/ml | Standard Deviation 10.0339424 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 22 | 31.56 ng/ml | Standard Deviation 13.41044369 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 2, Day 1 | 30.28 ng/ml | Standard Deviation 11.77497346 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 3, Day 1 | 27.49 ng/ml | Standard Deviation 13.31277582 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 4, Day 1 | 23.67 ng/ml | Standard Deviation 11.83849653 |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 1 | 31.22 ng/ml | Standard Deviation 14.57292009 |
Secondary
Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab
Sample medians of trough concentrations of denosumab will be calculated.
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
Population: The number of patients who contributed samples varied across cycles.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 3, Day 1 | 23.8 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 22 | 27.85 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 4, Day 1 | 23.7 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 15 | 20.7 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 1 | 20.3 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 2, Day 1 | 30.75 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 15 | 23.2 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 8 | 10.8 ng/ml |
| Cohort 1: Measurable | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 1 | 0 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 15 | 23.5 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 7, Day 1 | 27.95 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 1 | 0 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 8 | 9.34 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 15 | 18.75 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 1, Day 22 | 27.6 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 2, Day 1 | 27.3 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 3, Day 1 | 22.8 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 4, Day 1 | 21.6 ng/ml |
| Cohort 2: Resection | Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab | Serum denosumab (ng/ml): Cycle 6, Day 1 | 32.05 ng/ml |
Secondary
Response Rate (CR or PR) for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I)
Confidence intervals will be constructed using the approximate normal distribution of each of the estimates and their asymptotic variances.
Time frame: Up to 3 years post-treatment
Population: There were not any patients that met criteria for bone site