A Phase 1/2, Open Label, Multicenter Study to Investigate the Safety and Efficacy of Fadraciclib (CYC065), an Oral CDK 2/9 Inhibitor, in Subjects With Leukemias or Myelodysplastic Syndrome (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 入组人数
- 210
- 试验地点
- 2
- 主要终点
- Maximum tolerated dose
研究概览
简要总结
This is a 2-part, phase 1/2, open-label, multicenter study designed to evaluate the safety and efficacy of fadraciclib (formerly CYC065) administered orally BID. This study consists of Phase 1 and Phase 2 components in subjects with Leukemia or Myelodysplastic syndrome (MDS) who have progressed despite having standard therapy or for which no standard therapy exists.
详细描述
Phase 1 part of the study will consist of a dose-escalation and a dose-finding component.
Phase 2 will enroll subjects AML, CLL, or MDS, into 7 groups:
Group 1: Subjects with AML or MDS having marrow blasts over > 10%, who have experienced an inadequate response or progression on venetoclax combinations with either HMAs or low dose Ara-C or similar venetoclax combinations
Group 2: Fadraciclib: Subjects with AML or MDS relapsed/refractory having marrow blasts over > 10% with FLT3, KIT, MAPK pathway (N and K RAS, BRAF, PTPN11, NF1) mutations after at least 1 line of prior therapy.
Group 3: Fadraciclib: Subjects with CLL who have progressed on 2 or more lines of therapy, including a Bruton's tyrosine kinase (BTK) inhibitor and venetoclax.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Males or females aged ≥ 18 years.
- •a) AML/MDS with blasts > 10% in subjects who have had an inadequate response or progression to venetoclax combinations with either HMA or low dose Ara-C or similar venetoclax combinations. or b. CLL in subjects who have received at least 2 lines of therapy, including venetoclax and a BTK inhibitor, who require therapy as per iwCLL criteria.
- •Any prior therapy must have been completed at least 2 weeks prior to enrollment on this protocol, and the participant must have recovered to eligibility levels from prior toxicity
- •Hydroxyurea may be used for the first 14 days of Cycle 1 for peripheral blast control. Valproic acid not being used for seizure control should be stopped 72 hours before starting treatment with fadraciclib.
- •Any prior therapy with decitabine or azacitidine must have been completed at least 3 weeks prior to enrollment on this protocol.
- •Subjects who relapsed post-autologous or post-allogeneic transplant are eligible. Post-transplant subjects must be without active fungal disease or significant acute graft-versus-host disease.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Women of childbearing potential (WOCBP) must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to receiving the first dose and for 6 months after the last dose) if conception is possible during this interval.
- •Subjects must be able to swallow and retain orally administered medication and not have any clinically significant GI abnormalities that may alter the absorption, such as malabsorption syndrome or major resection of the stomach or bowels.
- •Subjects must be able to agree to and sign the informed consent and to comply with the protocol.
排除标准
- •Subjects with known active leptomeningeal involvement by AML.
- •Subjects who have not received vaccines for SARS-COV-2 within the last 3 months and have suspected signs and symptoms of COVID-19 or a recent history (within 14 days) of contact with any COVID-19 positive subject/isolation/quarantine or subjects with confirmed COVID-
- •Subjects with a history of another primary malignancy, other than:
- •Carcinomas in situ, e.g., breast, cervix, and prostate
- •Locally excised non-melanoma skin cancer
- •No evidence of disease from another primary cancer for 2 or more years and has not taken any anticancer treatment in 2 years.
- •Any other clinically significant acute or chronic medical or psychiatric condition or any laboratory abnormality that may increase the risk associated with study drug administration or may interfere with the interpretation of study results.
- •Diseases that significantly affect GI absorption of fadraciclib.
- •Subjects who have impaired cardiac function or clinically significant cardiac disease.
- •Presence of active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or GI perforation within 6 months of enrollment.
- •Presence of an active infection requiring IV antibiotics.
- •Presence of known history of human immunodeficiency virus-1/2 with uncontrolled viral load and on medications that may interfere with metabolism.
- •Presence of active hepatitis B virus (HBV) or hepatitis C virus (HCV).
- •Subject has received systemic anticancer therapy (including investigational therapy), radiotherapy, or immunotherapy < 14 days or 5 half-lives (whichever is shorter) prior to administration of Dose 1 of study drug on Day 1 or have not recovered from the side effects of such therapy.
- •Major surgery/surgical therapy for any cause within 4 weeks of the first dose.
研究组 & 干预措施
Phase I Dose escalation
Phase 1 = fadraciclib administered orally in escalating doses starting at 50mg bid MWF for 3 weeks of a 4-week cycle. Subsequent cohorts will escalate in dose and schedule until optimized phase 2 dose and schedule is achieved.
干预措施: fadraciclib (Drug)
Phase 2
Recommended fadraciclib phase 2 dose and schedule administered orally in 28-day cycles.
干预措施: fadraciclib (Drug)
结局指标
主要结局
Maximum tolerated dose
时间窗: 6 months
The incidence rate of dose-limiting toxicities (first cycle only) at each dose level
Overall Response Rate (ORR)
时间窗: 18 months
Assessment of response criteria according to iwCLL criteria for CLL/SLL and IWG criteria for AML and MDS.
次要结局
- Adverse events(24 months)