A Phase 1b/2, Open-label Clinical Study to Determine Preliminary Safety and Efficacy of Alvocidib When Administered in Sequence After Decitabine or Azacitidine in Patients With MDS
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 20
- 试验地点
- 23
- 主要终点
- Number of Participants With Adverse Events and Serious Adverse Events
研究概览
简要总结
Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML.
Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.
详细描述
PHASE 1b:
Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib dose will follow a standard 3+3 design with sequential cohorts of 3 patients treated with incrementally higher doses of alvocidib administered in sequence after decitabine (during dose escalation) or azacitidine until a dose-limiting toxicity (DLT) is observed and the MTD is established.
Once the MTD or preliminary RP2D of alvocidib administered via hybrid dosing is identified, 2 cohorts of at least 3 patients each will receive azacitadine followed by alvocidib administered as a 30-60 minute IV infusion.
Expansion at MTD Once the MTD or preliminary RP2D of alvocidib administered as a 30-to-60 minute IV infusion is determined, up to 25 patients will be enrolled in an Expansion cohort to receive alvocidib following azacitadine to confirm safety, explore potential biomarkers, and evaluate potential signals of alvocidib activity. Once this Expansion cohort is completed, the study will progress to Phase 2
PHASE 2:
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
- •Aged ≥18 years
- •Phase 1b Dose Escalation: Patients with previously untreated MDS and patients with MDS who received fewer than six (6) cycles of previous HMAs. Phase 1b Expansion: Untreated patients with de novo or secondary MDS. Phase 2: Untreated patients with de novo or secondary MDS
- •Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤2 at enrollment
- •Provide written informed consent prior to any study-related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)
- •Patients with a life expectancy of ≥3 months (90 days)
- •Patients with adequate major organ functions meeting the following criteria on the basis of laboratory data within 4 weeks (28 days) before enrollment (if multiple data are available, most recent data during the period):
- •Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range
- •Total bilirubin: ≤2× the ULN
- •Aspartate transaminase (AST) and alanine transaminase (ALT): ≤3× the ULN
- •Left ventricular ejection fraction (LVEF) >45% by echocardiogram or multigated acquisition (MUGA) scan
- •Be able to comply with the requirements of the entire study.
- •Patients with Revised International Prognostic Scoring System (IPSS-R) intermediate-, high-, and very high-risk MDS
排除标准
- •Presence of concomitant severe cardiovascular disease:
- •Patients who had myocardial infarction within 6 months (180 days) before enrollment
- •Patients with significant diseases at enrollment that may affect study treatment, such as New York Heart Association (NYHA) Functional Class III or IV heart disease, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade ≥3 arrhythmia, angina pectoris, abnormal electrocardiogram findings, interstitial pneumonia or pulmonary fibrosis
- •Presence of concomitant malignancy requiring chemotherapy or any malignancy (except basal and squamous cell carcinoma of the skin) for which the patient received chemotherapy within 6 months prior to enrollment. NOTE: Diagnosis of any previous or concomitant malignancy is thus not an exclusion criterion.
- •Presence of uncontrolled or uncontrollable infection(s); or ≥Grade 3 infection according to NCI CTCAE v5.0
- •Presence of any psychological, familial, sociological or geographical condition that, in the opinion of the investigator, could potentially hinder compliance with the study protocol and follow-up schedule
- •Patients with a dry tap on bone marrow aspiration before enrollment
- •Patients with concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease, or patients who require long-term systemic steroid therapy greater than the equivalent of 20 mg of prednisone daily (excluding therapy given on an 'as needed' [PRN] basis)
- •Patients with other documented malignancies within past year aside from synchronous or metachronous multiple cancers with a disease-free period of ≤5 years (excluding carcinoma in situ, mucosal carcinoma, or other such carcinomas curatively treated with local therapy)
- •Patients with ≥Grade 2 hemorrhage according to NCI CTCAE v5.0
- •Patients who have previously received alvocidib or another cyclin-dependent kinase 9 (CDK9) inhibitor
- •Patients who are pregnant or breastfeeding
- •Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception associated with a low failure rate prior to study entry, for the duration of study participation and for at least 6 months after the last dose of study drug. (Patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy, or bilateral tubal ligation / salphingectomy, or postmenopausal for at least 2 years.)
- •Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second effective method of contraception during the trial and for at least 3 months after the last administration of study treatment.
- •Patients who are inappropriate for participation in the study for other reasons in the opinion of the investigator or sub-investigator(s)
- •Patients with a known hypersensitivity to decitabine (those patients enrolled in escalation) or azacitidine or mannitol
- •Patients who have received erythropoietin-stimulating agents (ESAs) within 2 weeks (14 days) prior to Cycle 1/Day 1
结局指标
主要结局
Number of Participants With Adverse Events and Serious Adverse Events
时间窗: From the time of first dose to 30 days after the last dose, an average of 33.7 weeks.
Assessment of safety of alvocidib administered in combination with either decitabine (DEC) or azacitidine (AZA) by reporting of adverse events and serious adverse events
Tolerability of Alvocidib as Evaluated by Incidence of Dose Limiting Toxicities (DLTs) as Observed in Cycle 1
时间窗: Cycle 1 (28 days)
The DLTs are defined as follows based on the NCI CTCAE v5.0: Must be at least possibly related to Alvocidib; Any Gr 4 nonhematologic toxicity; Gr 3 nonhematologic toxicity that does not resolve to ≤Gr 2 in 48 hours; Gr 3 diarrhea, mucositis, nausea, or vomiting will be considered dose limiting only if resolution to ≤Gr 2 requires \>7 days; and ≥Grade 3 creatinine elevation that does not resolve to \<G2 within 7 days.
次要结局
- Determination of the Complete Response Rate(From the date of first treatment, every 8 weeks, for the first 6 cycles, for an average of 26 weeks)
- Improvement in Transfusion Dependence(Duration of study treatment up to 6 months)