A Phase 1 Study of AZD1775 in Combination With Belinostat in Relapsed and Refractory Myeloid Malignancies and Selected Untreated Patients With Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Recommended phase 2 dose (RP2D) for the combination of WEE1 inhibitor AZD1775 and belinostat, defined as the dose in which =< 1 out of 6 patients at highest dose level below the maximally administered dose experience dose-limiting toxicities (DLTs)
研究概览
简要总结
This phase I trial studies the side effects and best dose of WEE1 inhibitor AZD1775 and belinostat when given together in treating patients with myeloid malignancies that have returned after a period of improvement or have not responded to previous treatment or patients with untreated acute myeloid leukemia. WEE1 inhibitor AZD1775 and belinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVES:
I. To identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for a regimen combining WEE1 inhibitor AZD1775 (AZD1775) with belinostat in patients with refractory/relapsed acute myeloid leukemia (AML), chronic myeloid leukemia in blast crisis (CML-BC), or intermediate-2 or high-risk myelodysplastic syndrome (MDS), and selected previously untreated poor-prognosis patients with AML.
SECONDARY OBJECTIVES:
I. To describe the toxicities of this regimen. II. To observe and record anti-tumor activity. III. If responses are observed, to determine what relationship, if any, exists between such responses and tumor protein 53 (p53)/fms-related tyrosine kinase 3 (FLT3) mutational status.
IV. To describe pharmacokinetic (PK) interactions, if any, between AZD1775 and belinostat.
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
- •Patients must have one of the following, histologically or cytologically confirmed:
- •Acute myeloid leukemia (AML) [non- acute promyelocytic leukemia (APL) AML]
- •If previously treated:
- •AML that is relapsed or refractory to at least one prior line of therapy
- •If previously untreated, must meet all of the following:
- •>= 60 years of age
- •Secondary or therapy-related AML
- •Does NOT bear favorable cytogenetic and/or molecular features, eg, core-binding factor abnormalities, FLT3 Internal Tandem Duplication (FLT3-ITD) negative/NPM1 mutated, biallelic CCAAT/enhancer binding protein alpha (CEBPA) mutation without FLT3-ITD
- •Chronic myeloid leukemia blast crisis (CML-BC)
- •Relapsed or refractory to at least one Bcr-Abl-TKI-containing regimen
- •Myelodysplastic syndrome (MDS), must meet all of the following:
- •Higher risk MDS [intermediate-2 or high risk by the original International Prognostic Scoring System (IPSS)]
- •Relapsed, refractory, or intolerant to at least one prior line of therapy containing hypomethylating agents (deoxyribonucleic acid [DNA] methyltransferase inhibitors)
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
- •Total bilirubin =< 1.5 × upper limit of normal (ULN) for the laboratory unless resulting from hemolysis
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × ULN for the laboratory
- •Creatinine within normal limits for the laboratory OR creatinine clearance >= 60 mL/min/1.73 m^2 (estimated glomerular filtration rate [eGFR]) for patients with creatinine levels above the ULN for the laboratory
- •Human immunodeficiency virus (HIV)-infected persons are eligible if they meet other eligibility criteria including the following:
- •No prior acquired immune deficiency syndrome (AIDS)-defining condition other than cluster of differentiation (CD)4+ cells nadir < 200/mm^3
- •Pre-leukemia CD4+ cell count >= 250/mm^3
- •Willing to adhere to antiretroviral therapy regimen with minimal overlapping toxicity and PK interactions with the experimental agents in this study; no zidovudine- and no ritonavir-containing regimens and no 3-drugs-in-1 pill regimens containing pharmacologic boosters are allowed; recommended regimens are integrase inhibitors combined with tenofovir and emtricitabine
- •Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of AZD1775 and belinostat administration
- •Ability to swallow medication
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Clinical picture indicative of leukostasis or evidence of disseminated intravascular coagulopathy
- •Other investigational agent within 3 weeks prior to initiation of study therapy
- •Ongoing toxicities >= grade 2 from prior therapy
- •Acute promyelocytic leukemia (APL, M3)
- •Active central nervous system (CNS) leukemia
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or belinostat
- •Stem cell transplant within previous 3 months prior to initiation of study therapy
- •Major surgical procedures =< 28 days before beginning study treatment or minor surgical procedures =< 7 day before beginning study treatment; no waiting required after placement of a vascular access device
- •Uncontrolled infection
- •Pregnant or nursing; women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study therapy
- •Note: Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AZD1775/belinostat
- •Circulating blast count >= 50,000/uL within the week preceding enrollment
- •Current candidacy for a potentially curative allogeneic stem cell transplant, unless declined
- •Corrected QT (QTc) interval >= 450 ms (ie, grade 1 or higher) on electrocardiogram (ECG) prior to initiation of study treatment
- •If baseline QTc on screening ECG is >= 450 ms (ie, grade 1 or higher):
- •Check potassium and magnesium serum levels
- •Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm QTc interval
- •For patients with baseline heart rate (HR) < 60 beats per minute (bpm) or > 100 bpm, manual measurement of QT interval by cardiologist is required, with Fridericia correction applied to that manual measurement to determine the QTc for eligibility consideration
- •Note: For patients with HR 60-100 bpm, manual measurement of QTc interval and use of Fridericia calculation is NOT required
- •Any of the following related to risk of torsades de pointes and sudden cardiac death:
- •History of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, or resuscitated cardiac arrest unless currently addressed with an implanted cardiac defibrillator
- •Concomitant treatment with an anti-arrhythmic agent to prevent or control arrhythmia; agents used for rate-control of atrial fibrillation are permitted provided that they are not prohibited due to potential drug interactions
- •Known congenital long QT syndrome
- •Second degree atrioventricular (AV) block type II, third degree AV block, or ventricular rate < 50 bpm or > 120 bpm
- •Unstable angina, myocardial infarction or New York Heart Association (NYHA) class III/IV congestive heart failure within 30 days preceding study enrollment
- •Ongoing or planned treatment with any of the following:
- •Atorvastatin
- •Strong inhibitors or inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4); as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- •If any of these agents have been used, patients must be off them for >= 2 weeks before starting study treatment
- •Any known UGT1A polymorphism, heterozygous or homozygous
- •History of prior therapy with belinostat or AZD1775
- •Active gastrointestinal (GI) conditions that might predispose to drug intolerance or poor drug absorption
- •Receiving any other therapies for cancer treatment (with the exception of gonadotropin-releasing hormone [GnRH] agonists for prostate cancer); Note: hydroxyurea is allowed before initiation of study treatment and for the first 5 days of study treatment
- •Diagnosis or treatment for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy
- •Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk, interfere with the patient's participation in the study, or hinder evaluation of study results
研究组 & 干预措施
Treatment (belinostat, WEE1 inhibitor AZD1775)
Patients receive belinostat IV over 30-90 minutes QD on days 1-5 and 8-12 and WEE1 inhibitor AZD1775 PO QD on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Responding patients with CR, CRi, CRc, or CRm and do not go on to have stem cell transplant may only continue treatment for 3-4 additional courses after response.
干预措施: Adavosertib (Drug)
Treatment (belinostat, WEE1 inhibitor AZD1775)
Patients receive belinostat IV over 30-90 minutes QD on days 1-5 and 8-12 and WEE1 inhibitor AZD1775 PO QD on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Responding patients with CR, CRi, CRc, or CRm and do not go on to have stem cell transplant may only continue treatment for 3-4 additional courses after response.
干预措施: Belinostat (Drug)
Treatment (belinostat, WEE1 inhibitor AZD1775)
Patients receive belinostat IV over 30-90 minutes QD on days 1-5 and 8-12 and WEE1 inhibitor AZD1775 PO QD on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Responding patients with CR, CRi, CRc, or CRm and do not go on to have stem cell transplant may only continue treatment for 3-4 additional courses after response.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (belinostat, WEE1 inhibitor AZD1775)
Patients receive belinostat IV over 30-90 minutes QD on days 1-5 and 8-12 and WEE1 inhibitor AZD1775 PO QD on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Responding patients with CR, CRi, CRc, or CRm and do not go on to have stem cell transplant may only continue treatment for 3-4 additional courses after response.
干预措施: Pharmacological Study (Other)
结局指标
主要结局
Recommended phase 2 dose (RP2D) for the combination of WEE1 inhibitor AZD1775 and belinostat, defined as the dose in which =< 1 out of 6 patients at highest dose level below the maximally administered dose experience dose-limiting toxicities (DLTs)
时间窗: 21 days
Patients' treatment dosing level, dose modification, DLTs, and evaluability for DLTs will be listed and summarized by basic descriptive statistics (such as frequency and proportion). DLTs will be assessed according to the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
次要结局
- Incidence of toxicity graded according to the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0(Up to 30 days after completion of study treatment)
- Changes in candidate biomarker levels (including p-Wee1, p-cdc2 and gamma-H2A.X) in bone marrow and/or blood samples(Baseline to 24 hours after first dose of study treatment)
- Time to response(From registration to the time of documentation of tumor response, assessed up to 2 years)
- Response rate (complete remission [CR] + CR with incomplete blood count recovery [CRi] + cytogenetic CR [CRc] + molecular CR [CRm]) according to International Working Group and European Leukemia Net criteria(Up to 2 years)
- p53 and FLT3 mutation status(Up to 24 hours after first dose of study treatment)
- Pharmacokinetic (PK) parameters (area under the curve [AUC], volume of distribution [Vd], peak concentration [Cmax], time to peak concentration [Tmax], and half-life [t1/2]) of belinostat(Day 1, course 1: pre-treatment, 5 minutes prior to the end of the belinostat infusion, 15 minutes (min), 30 min, 1 hour (hr), 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr after the end of the belinostat infusion)
- Duration of response (in patients with (complete remission [CR] + CR with incomplete blood count recovery [CRi] + cytogenetic CR [CRc] + molecular CR [CRm])(From documentation of tumor response to disease progression or death, whichever occurs first, assessed up to 2 years)
- PK parameters (area under the curve [AUC], volume of distribution [Vd], peak concentration [Cmax], time to peak concentration [Tmax], and half-life [t1/2]) of WEE1 inhibitor AZD1775(Day 1, course 1: pre-treatment, and 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr after WEE1 inhibitor AZD1775 administration)