Phase 2 Study of Denosumab (NSC# 744010), a RANK Ligand Antibody, for Recurrent or Refractory Osteosarcoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 279
- 主要终点
- Disease Control Rate (Cohort I)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 11 Years 至 49 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
结局指标
主要结局
Disease Control Rate (Cohort I)
时间窗: 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.
Disease Control Rate (Cohort II)
时间窗: 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.
Response Evaluation Criteria in Solid Tumors (RECIST) Response (Complete Response [CR] or Partial Response [PR] vs Not CR or PR) (Cohort I)
时间窗: 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.
次要结局
- 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)
- Response Rate (CR or PR) for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I)(Up to 3 years post-treatment)
- 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)
- 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)
- Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0(Minimum of 2 years)
- Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort I)(At 4 months)
- Disease Control Rates for Patients With Recurrent Osteosarcoma Limited to Bone (Cohort II)(At 12 months)
- 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)