Metronomic Cyclophosphamide and Methotrexate Combined With Zoledronic Acid and Sirolimus in Patients With Advanced Solid Tumor With Bone Metastasis and Advanced Pretreated Osteosarcoma. A Phase Ib Study From the French Sarcoma Group
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 3
- 主要终点
- Dose Escalation Part: Number of Dose-Limiting Toxicities (DLTs) at Each Dose Level on Cycle 1
研究概览
简要总结
This is a prospective open-labeled phase I trial based on a dose escalating study design assessing two dose levels of sirolimus when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) followed by an expansion cohort once the Maximum Tolerated Dose (MTD) is established.
详细描述
The dose escalation part of the trial will be concerned on adults with advanced solid tumor with bone metastasis and young and adult patients with unresectable locally advanced or metastatic osteosarcoma.
The Expansion cohort will be conducted on young and adult patients with unresectable locally advanced or metastatic osteosarcoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 13 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Advanced solid tumor with radiologically proven bone metastasis, (dose escalation part)
- •Patients with osteogenic osteosarcoma (dose escalation part and expansion cohort) histologically confirmed by central review
- •Metastatic or unresectable locally advanced disease, not eligible for alternative local treatment (radiotherapy for instance)
- •Age > 18 years for patients with solid tumor and ≥ 13 years for patients with osteosarcoma
- •ECOG, performance status ≤ 1
- •Life expectancy > 3 months
- •Measurable disease according to RECIST v1.
- •At least one site of disease must be uni-dimensionally ≥ 10 mm
- •Patients must have histologically confirmed diagnosis of locally advanced and/or metastatic solid tumors, which are not amenable to standard treatment, including for patients with osteosarcoma conventional agents such as anthracyclines, platinum salts, ifosfamide and/or methotrexate
- •At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy
- •Adequate haematological, renal, metabolic and hepatic function:
- •Haemoglobin ≥ 10 g/dl (patients may have received prior red blood cell transfusion, if clinically indicated); leucocytes ≥ 3 x 10^9/l, absolute neutrophil count ≥ 1.5 x 10^9/l, and platelet count ≥ 120 x 10^9/l.
- •Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 x upper limit of normality (ULN)
- •Total bilirubin ≤ 1.5 x ULN
- •Calculated creatinine clearance > 40 ml/min/1.73 m² (according to MDRD formula)
- •Creatine phosphokinase ≤ 2.5 x ULN
- •Albumin > 25 g/l
- •No prior or concurrent malignant disease diagnosed or treated in the last 2 years except adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
- •Recovery to grade ≤ 1 from any adverse event derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the NCI-CTCAE, version 4
- •Patients with a French social security in compliance with the French law relating to biomedical research
- •Voluntarily signed and dated written informed consent prior to any study specific procedure
- •Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment
排除标准
- •Previous treatment with sirolimus
- •Concomitant diseases/conditions:
- •Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions
- •Unstable cardiac disease, pulse oximetry saturation < 90% at rest
- •Clinically significant immunodeficiency, such as HIV or active Hepatitis B or C
- •History of auto-immune disease, transplantation
- •Central nervous system malignancy
- •Men or women of childbearing potential who are not using an effective method of contraception; women who are pregnant or breast feeding
- •Patients receiving any substances that are inhibitors or inducers of CYP450 3A4
- •Ongoing or recent (<6 weeks) dental problem, including any severe tooth or jaw infection (mandible and maxilla), dental trauma, dental or stomatological surgery (implants). Current dental cares are allowed
- •History of maxillary osteonecrosis or delayed healing after dental surgery
- •Participation to a study involving a medical or therapeutic intervention in the last 30 days
- •Previous enrolment in the present study
- •Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons
- •Known hypersensitivity to any involved study drug or any of its formulation components
- •Patients receiving live vaccines within 30 days prior to the first dose of study therapy and while participating in study
研究组 & 干预措施
Sirolimus combined with CP, MT and ZA
Drug : Metronomic Cyclophosphamide, Methotrexate, Sirolimus, Zoledronic acid Assessment of the maximum tolerated dose of sirolimus Cyclophosphamide, Methotrexate and Sirolimus will be administrated orally. Zoledronic Acid will be administrated by infusion (IV).
干预措施: Sirolimus combined with CP, MT and ZA (Drug)
结局指标
主要结局
Dose Escalation Part: Number of Dose-Limiting Toxicities (DLTs) at Each Dose Level on Cycle 1
时间窗: During the first cycle (28 days)
A DLT is defined as an adverse event (AE) or laboratory abnormality that fulfills the criteria below: * Is considered to be at least possibly related to the study treatment * Occurs during the first cycle of treatment * Is unrelated to disease, disease progression, inter-current illness, or concomitant medications * Meets one of the criteria below, graded as outlined or according to NCI CTCAEv4.3: * Grade 4 non-haematological toxicity (not laboratory) * Grade 3 non-haematological toxicity \> 3 days (not laboratory) (except for asthenia, 1rst episode of nausea/vomiting without maximal symptomatic/prophylactic treatment) * Grade ≥ 3 non-hematologic laboratory value if medical intervention is required to treat the patient, or the abnormality leads to hospitalization, or the abnormality persists for \> 1 week * Grade ≥ 3 hematologic toxicity \> 3 days (except for lymphopenia) * Grade 4 lymphopenia * Confirmed febrile neutropenia
Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, in Terms of 6-month Non-progression Rate
时间窗: 6-month non-progression rate as per RECIST v1.1
6-month non-progression rate defined as the rate of complete or partial response or stable disease at 6 months using RECIST v1.1 : * Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions and also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD * Unevaluable : patients stopped the treatment before tumor assessment.
次要结局
- Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1(Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 4 months.)
- Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS)(1-year Progression-free survival (PFS) as per RECIST v1.1)
- Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS)(1-year Overall Survival (OS) as per RECIST v1.1)
- Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1(Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 4 months.)
- Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS) as Per RECIST v1.1(1-year Progression-free survival (PFS) as per RECIST v1.1)
- Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS) as Per RECIST v1.1(1-year Overall Survival (OS) as per RECIST v1.1)