A Phase II Study of SGI-110 in Philadelphia-Negative Myeloproliferative Neoplasms
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Number of Participants With Hematological Response, as Measured by Any One or More of the Following Response Assessments: IWG-MDS and IWG-MF Criteria as Accurate and Appropriate.
研究概览
简要总结
- This is an open label single-arm, single-institution stud to evaluate the efficacy and safety of SGI-110 in Philadelphia chromosome negative (Ph-) Myeloproliferative Neoplasms (MPN) (excluding PV, ET and primary/secondary myelofibrosis). The study will enroll approximately 50 patients at the Weill Cornell Medical College.
- Enrollment onto this clinical study is expected to be completed in approximately 36 months. The total study duration will depend on individual response, evidence of disease progression and tolerance. Participants will be followed monthly for six months after removal from study or until death, whichever occurs first.
Key eligibility:
- Confirmed diagnosis of Ph- MPN and had
- No chemotherapy or radiation treatment within 2 weeks prior to study entry.
- Subjects meet other protocol-defined criteria related to baseline screening procedures.
详细描述
The active metabolite of SGI-110 (2'-deoxy-5-azacytidylyl-(3'→5')-2'-deoxyguanosine sodium salt), a dinucleotide, is decitabine, an FDA-approved agent for the treatment of myelodysplastic syndromes. SGI-110 is resistant to modification by cytidine deaminase, a common pathway of decitabine metabolism and deactivation[1]. The molecular weight of SGI-110 and decitabine are 580 Da and 228 Da, respectively. Therefore, the molar equivalent dose of 1 mg of decitabine is approximately 2.5 mg of SGI-110. SGI-110's activity was demonstrated with the same preclinical pharmacodynamic assays used to demonstrate decitabine's efficacy e.g., re-expression of p15, p16, and MLH1 and induction of fetal hemoglobin, in vivo. In xenograft studies, SGI-110 demonstrates promising preclinical activity in both hematologic and solid tumors.
In vitro evidence suggests that SGI-110 has a longer half-life than decitabine in the presence of cytidine deaminase. These promising observations suggest that SGI-110 may have improved pharmaceutical properties and biological activities that could extend decitabine's current clinical utility. SGI-110 has shown to be better tolerated in mice than decitabine and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding EJ6 human bladder cancer tumor growth in athymic mice[2].
SGI-110 has been developed for subcutaneous administration. SGI-110 is pharmacologically active both in vitro and in vivo in a variety of tumor cells and murine xenograft models when administered subcutaneously. Treatment is well tolerated via the subcutaneous route in murine xenografts. When administered subcutaneously to non-human primates, SGI-110 releases decitabine slowly compared to other species, possibly prolonging the effect over longer periods. SGI-110 has been developed as a non-aqueous formulation to ensure formulation stability.
SGI-110 has been studied in a first-in-human, single-agent study (SGI-110-01).5 This study was a Phase 1/2, dose escalation, multicenter study of two subcutaneous regimens of SGI-110 in subjects with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). This study had two parts, a Dose Escalation Segment and a Dose Expansion Segment. The study evaluated the biological activity, preliminary safety, and efficacy of SGI-110 with two dosing schedules in intermediate to high risk MDS or relapsed or refractory AML subjects, while the Dose Expansion Segment further evaluated safety and efficacy at the recommended dose. The study was based on a 3 + 3 design within each regimen. Eligible subjects were randomized to receive 1 of 2 dosing regimens of SGI-110 with the following starting doses: Regimen 1: 3 mg/m2/day subcutaneously on Days 1-5 of a 28-day course, Regimen 2: 6 mg/m2 subcutaneously Weekly x 3 on Days 1, 8, 15 of a 28-day course. The minimum dose achieving maximal biological activity or biologically effective dose (BED) for the daily regimen was reached at 60 mg/m2 daily on Days 1-5.
Study disease: MPN
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •3.1.1 Participants must have confirmed diagnosis of Philadelphia chromosome negative MPN neoplasm based on WHO classification (reference) including Chronic Neutrophilic Leukemia (CNL), atypical Chronic Myeloid Leukemia (aCML), Chronic Myelomonocytic Leukemia (CMML), MPN/MDS overlap syndromes, accelerated phase myelofibrosis and MPN unclassifiable.
- •3.1.2 Age minimum of 18 years. Because no dosing or adverse event data are currently available on the use of SGI-110 in participants <18 years of age, children are excluded from this study but may be eligible for future pediatric trials.
- •3.1.3 ECOG performance status <3
- •3.1.4 Participants must have normal organ function as defined below:
- •Total bilirubin < or = 1.5 X institutional upper limit of normal unless attributable to underlying disease, hemolysis or documented Gilbert's syndrome
- •AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal unless attributable to underlying disease
- •Creatinine < 1.5add < or = 1.5X institutional upper limit of normal or creatinine clearance add using Cockcroft Gault > 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.
- •LVEF < 40 % is allowed as long as there is no NY class III/IV heart failure or uncontrolled arrhythmias.
- •3.1.5 The effects of SGI-110 on the developing human fetus are unknown. For this reason and because oncological agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- •3.1.6 Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •3.2.1 Participants who have had any chemotherapy (investigational or FDA approved) (hydroxyurea is permitted) or radiotherapy within 2 weeks prior to study entry or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
- •3.2.2 Participants may not be treated with any other investigational agents while on this study unless approved by the principal investigator AND the sponsors of BOTH investigational agents.
- •3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine or SGI-
- •3.2.4 Uncontrolled intercurrent illness including, but not limited to, infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnant women are excluded from this study because SGI-110 is a hypomethylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with SGI-110, breastfeeding should be discontinued.
- •3.2.5 Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
研究组 & 干预措施
Open Label-Single Arm
This is a single arm, open-label study of SGI-110 in patients with MPN. SGI-110 will be administered subcutaneously at a dose of 60 mg/m2 on days 1-5, repeated every 28 days. Toxicity will be evaluated using the NCI Common Terminology Criteria for Adverse Events Active Version 4. The frequency of toxicities per organ system will be tabulated using descriptive statistics. All patients who receive any amount of the study drug will be evaluable for toxicity
干预措施: SGI-110 (Drug)
结局指标
主要结局
Number of Participants With Hematological Response, as Measured by Any One or More of the Following Response Assessments: IWG-MDS and IWG-MF Criteria as Accurate and Appropriate.
时间窗: At the end of cycles 3, 6 and 12 - up to approximately 336 days
The response to treatment will be measured from baseline through 12 cycles. A response assessment will be performed after cycle 3, cycle 6 and cycle 12. The response will be measured by IWG-MDS (International working group - Myelodysplastic Syndrome), which is a set of criteria that dictates what response a patient with MDS has had to a treatment; IWG-MF (International Working Group - Myelofibrosis) which is a set of criteria that dictates what response a patient with MF has had to a treatment. Both sets of criteria utilize the following parameters to asses response: Results from blood tests; bone marrow biopsies; physical exams to look at spleen and liver size; and symptoms. All responses will be recorded in our database and the best response to treatment will be reported. A cycle is at least 28 days, which can be extended past day 28 in order to allow physicians decision to delay next cycle based on the patients clinical needs.
次要结局
- Number of Participants With Change in Quality of Life (QoL) Scores as Defined by Myeloproliferative Neoplasms Symptoms Assessment Form (MPN-SAF).(Baseline, at the beginning of each new cycle - approximately every 28 days for up to 700 days)