Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma

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.

• Denosumab (Biological), also known as AMG 162, AMG-162, Denosumab Biosimilar MW032, Denosumab Biosimilar QL1206, Denosumab Biosimilar TK-006, Prolia, TK-006, Xgeva: Given SC
• Laboratory Biomarker Analysis (Other): Correlative studies
• Pharmacological Study (Other): Correlative studies

Primary outcomes

• 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 outcomes

• 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.
• 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
• 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
• 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.
• 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.

Sex: All, ages: 11 Years to 49 Years

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

Participant flow

Outcome results

• Disease Control Rate (Cohort I) (Primary), Number, participants: Cohort 1: Measurable 1
• Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I) (Primary), Number, participants: Cohort 1: Measurable 0
• Disease Control Rate (Cohort II) (Primary), Number, participants: Cohort 2: Resection 10
• Pharmacokinetic (PK) Parameters: Mean of Trough Concentrations of Denosumab (Secondary), Mean, ng/ml: Cohort 1: Measurable 0 +/- 0; Cohort 2: Resection 0 +/- 0
• Pharmacokinetic (PK) Parameters: Median of Trough Concentrations of Denosumab (Secondary), Median, ng/ml: Cohort 1: Measurable 0 (0 to 0); Cohort 2: Resection 0 (0 to 0)
• Pharmacodynamic (PD) Parameters of Denosumab: Serum C-telopeptide (Secondary), Mean, pg/ml: Cohort 1: Measurable 1713 +/- 1857; Cohort 2: Resection 944.5 +/- 543
• Pharmacodynamic (PD) Parameters of Denosumab: Urine N-telopeptide to Creatinine Ratio (Secondary), Mean, nMol BCE/mmol creatinine: Cohort 1: Measurable 322.2 +/- 307; Cohort 2: Resection 190.7714 +/- 283
• Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Secondary), Number, cycles: Treatment (Denosumab) 1
• Response Rate (CR or PR) for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) (Secondary)
• Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I) (Secondary)
• Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II) (Secondary), Number, proportion of patients: Cohort 2: Resection 0.667 (0.195 to 0.904)

Adverse events

Time frame: Through completion protocol therapy planned as 728 days after study enrollment

Serious adverse events by term

Other adverse events by term

41 more sites not listed.

• Study Protocol and Statistical Analysis Plan (PDF, 2018-10-22)

• Katherine A Janeway, Principal investigator, Children's Oncology Group

NIH grants: U10CA180886