A Phase 1/2A, Open Label Dose Escalation and Cohort Expansion Study of Orally Administered CA-4948 (IRAK4i) as a Monotherapy in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Curis Inc.
- 入组人数
- 70
- 试验地点
- 32
- 主要终点
- Phase 1: Safety measured by adverse events (AEs), dose-limiting toxicities (DLTs) electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations
研究概览
简要总结
Phase 1 • To evaluate the safety and tolerability of CA-4948 in patients with relapsed / refractory (R/R) acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndrome (hrMDS) • To identify maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D)
Phase 2a: To assess anti-cancer activity of CA-4948 at RP2D in patients with R/R AML with FMS-like tyrosine kinase-3 (FLT-3) mutations, and patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1
详细描述
The primary objective of the Phase 1 portion of the study is to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for emavusertib in monotherapy in patients with AML, intermediate-2, high risk, or every high risk MDS based on the safety and tolerability, dose-limiting toxicities (DLTs), and Pharmacokinetic (PK)/Pharmacodynamic (PD) findings.
The primary objective of the Phase 1b portion of the study is to determine MTD and RP2D for emavusertib in combination with azacitidine (AZA) in treatment naïve patients with hrMDS or in combination with venetoclax (VEN) in R/R patients with AML or hrMDS after first line treatment based on the safety and tolerability, DLTs and PK and pharmacodynamic findings. Note, this portion of the study is no longer enrolling patients.
The primary objective of the Phase 2a portion of the study (emavusertib monotherapy expansion) is to assess anti-cancer activity of CA-4948 at the RP2D in patients with R/R AML with FMS-like tyrosine kinase-3 (FLT3) mutations, or patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1.
Emavusertib is formulated as tablets for twice daily oral administration. Each treatment cycle will be 28 days in length and repeated in the absence of toxicity. Patients who tolerate emavusertib may continue to receive emavusertib until progression of disease, intolerable toxicity, lack of clinical benefit, withdrawal from the trial, or study termination.
The emavusertib starting dose level will be 200 milligrams (mg) twice daily (BID) which was determined to be safe, capable of achieving relevant levels of drug exposure as well as demonstrating signs of biologic activity and clinical efficacy in an ongoing study (Study CA-4948-101). For phase 1, emavusertib is taken daily for 28 days of a 28 day cycle. For Phase 1b, emavusertib is taken daily for 21 days of a 28 day cycle in combination with venetoclax.
研究设计
- 研究类型
- Interventional
- 分配方式
- Not Applicable
- 主要目的
- Phase 2a
- 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 and females ≥18 years of age
- •Life expectancy of at least 3 months
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1
- •Cytomorphology based confirmed diagnosis of MDS or AML (as per World Health Organisation [WHO] 2016 classification) with the following characteristics.
- •Phase 1 Dose Escalation (Monotherapy)
- •AML (primary or secondary, including treatment-related) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation).
- •Higher-risk R/R MDS that are considered resistant/refractory following at least 2 to 3 cycles of hypomethylating agent (HMA) or evidence of early progression
- •Phase 2a Dose Expansion (Monotherapy)
- •Patients with:
- •R/R AMLwith FLT3 mutations who have been previously treated with a FLT3 inhibitor
- •R/R AML with spliceosome mutations of SF3B1 or U2AF1
- •R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1
- •Number of prior treatments: 1 or 2
- •Acceptable organ function at screening
- •Ability to swallow and retain oral medications
- •Negative serum pregnancy test in women of childbearing potential
- •Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 180 days after the last dose of emavusertib
- •Willing and able to provide written informed consent and comply with the requirements of the trial
- •Able to undergo serial bone marrow sampling and peripheral blood sampling
排除标准
- •Diagnosed with acute promyelocytic leukemia (APL, M3)
- •Has known active central nervous system (CNS) leukemia
- •Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of emavusertib, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of emavusertib
- •Chronic myeloid leukemia (CML)
- •Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 3 weeks (or 5 half-lives) prior to start of emavusertib.
- •Localized radiation or surgical resection of skin cancers allowed.
- •Use of any investigational agent within 3 weeks or 5 half-lives, whichever is shorter, prior to start of emavusertib
- •Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤ 1 within 7 days prior to start of emavusertib.
- •Known allergy or hypersensitivity to any component of the formulation of emavusertib
- •Major surgery, other than diagnostic surgery, <28 days from the start of emavusertib; minor surgery <14 days from the start of emavusertib
- •Patients with active advanced malignant solid tumors
- •Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
- •Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive or Hepatitis C virus (HCV) infection <6 months prior to start of emavusertib unless viral load is undetectable, or HCV with cirrhosis
- •Uncontrolled or severe cardiovascular disease including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, or QTc with Fridericia's correction (QTcF) that is unmeasurable or > 450 milliseconds (msec) on Screening electrocardiogram (ECG)
- •Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib
- •Pregnant or lactating
- •Systemic fungal, bacterial, viral, or other infection that is not controlled
- •Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or emavusertib administration
研究组 & 干预措施
Emavusertib (CA-4948) dose escalation
Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Emavusertib (Drug)
Emavusertib dose escalation + Venetoclax
The starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level.
干预措施: Venetoclax (Drug)
Emavusertib dose escalation + Venetoclax
The starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level.
干预措施: Emavusertib (Drug)
Emavusertib monotherapy dose expansion
The Expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease.
干预措施: Emavusertib (Drug)
结局指标
主要结局
Phase 1: Safety measured by adverse events (AEs), dose-limiting toxicities (DLTs) electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations
Phase 1: Safety measured by adverse events (AEs), dose-limiting toxicities (DLTs) electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations
Phase 2a: Clinical response in AML or hrMDS assessed as follows: • AML: Proportion of patients who achieve CR + CRh • hrMDS: ORR (CR + PR)
Phase 2a: Clinical response in AML or hrMDS assessed as follows: • AML: Proportion of patients who achieve CR + CRh • hrMDS: ORR (CR + PR)
次要结局
- Phase 1: PK parameters of CA 4948 measured by maximum plasma concentration (Cmax), trough plasma concentration (Cmin), time to Cmax (Tmax,) area under the concentration-time curve from 0-24 hours (AUC 0-24), area under the concentration-time curve from 0 to infinity (AUC 0-inf), and half-life (T ½)
- Phase 1: Clinical response in AML :- Proportion of patients who achieve complete response (CR) + complete response with partial hematological recovery (CRh) - Proportion of patients who achieve complete response with incomplete hematological recovery (CRi), or CR, or CRh, or partial response (PR), or morphologic leukemia-free state (MLFS) - Duration of response (DOR) - Time to response
- Phase 1: Clinical response in hrMDS: - Overall response rate (ORR): proportion of patients who achieve CR or PR - DOR - Time to response
- Phase I: Transfusion independence in AML or hrMDS
- Phase 2a: Safety measured by AEs, ECGs, chemistry and hematology laboratory values, vital signs, and physical examinations
- Phase 2a: Clinical response in AML or hrMDS assessed as follows:- Proportion of patients with AML who achieve CR, or CRh, or CRi - Proportion of patients with hrMDS who achieve CR, or PR, or mCR, with or without hematological improvement - DOR - Time to responses - Transfusion independence - Overall survival (OS)
研究者
Catherine Wang
Scientific
Curis Inc.