临床试验/NCT03416179

NCT03416179已完成3 期

A RANDOMIZED (1:1), DOUBLE-BLIND, MULTI-CENTER, PLACEBO CONTROLLED STUDY EVALUATING INTENSIVE CHEMOTHERAPY WITH OR WITHOUT GLASDEGIB (PF-04449913) OR AZACITIDINE (AZA) WITH OR WITHOUT GLASDEGIB IN PATIENTS WITH PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA

Pfizer149 个研究点分布在 6 个国家目标入组 730 人开始时间: 2018年4月20日最近更新: 2023年4月21日

适应症

干预措施

试验速览

阶段: 3 期
状态: 已完成
发起方: Pfizer
入组人数: 730
试验地点: 149
主要终点: Intensive Study: Overall Survival (OS)

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).

详细描述

Two separate registration trials conducted under one protocol number are proposed to adequately and independently evaluate the addition of glasdegib in intensive and non-intensive chemotherapy populations. Each study will have an experimental treatment arm and a placebo arm. Endpoints are the same for each study except where specifically indicated.

Assignment to the Intensive Study or the Non-Intensive Study will be made by the Investigator based on the 2017 European LeukemiaNet (ELN) recommendations.

Study B1371019 is a randomized (1:1), double-blind, multi-center, placebo controlled study of chemotherapy in combination with glasdegib versus chemotherapy in combination with placebo in adult patients with previously untreated AML.

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Parallel
主要目的: Treatment
盲法: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

盲法说明

Double blind study.

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

•Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the Intensive and Non Intensive study (unless where indicated):
•Subjects with untreated AML according to the World Health Organization (WHO) 2016 Classification2, including those with:
•AML arising from MDS or another antecedent hematologic disease (AHD).
•AML after previous cytotoxic therapy or radiation (secondary AML).
•18 years of age (In Japan, 20 years of age).
•Adequate Organ Function as defined by the following:
•Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 3 x upper limit of normal (ULN), excluding subjects with liver function abnormalities due to underlying malignancy.
•Total serum bilirubin 2 x ULN (except subjects with documented Gilbert's syndrome).
•Estimated creatinine clearance 30 mL/min as calculated using the standard method for the institution.
•QTc interval 470 msec using the Fridericia correction (QTcF).
•All anti cancer treatments (unless specified) should be discontinued 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines.
•For control of rapidly progressing leukemia, all trans retinoic acid (ATRA), hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after the first dose of glasdegib.
•Serum or urine pregnancy test (for female subjects of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) negative at screening.
•Male and female subjects of childbearing potential and at risk for pregnancy must agree to use at least one highly effective method of contraception throughout the study and for 180 days after the last dose of azacitidine, cytarabine, or daunorubicin; and the last dose of glasdegib or placebo, whichever occurs later.
•Female subjects of non childbearing potential must meet at least 1 of the following criteria:
•Have undergone a documented hysterectomy and/or bilateral oophorectomy;
•Have medically confirmed ovarian failure; or
•Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state.
•All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
•Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.
•Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
•Subjects who are willing and able to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow [BM] assessments).

排除标准

•Subjects with any of the following characteristics/conditions will not be included in the study:
•Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016 classification).
•AML with BCR ABL1 or t(9;22)(q34;q11.2) as a sole abnormality.
•Complex genetics may include t(9;22) cytogenetic translocation.
•Subjects with known active CNS leukemia.
•Participation in other clinical studies involving other investigational drug(s) (Phases 1 4) within 4 weeks prior study entry and/or during study participation.
•Subjects known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
•Subjects with another active malignancy on treatment with the exception of basal cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or concurrent malignancies will be considered on a case by case basis.
•Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias (including sustained ventricular tachyarrhythmia), right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms.
•Subjects with an active, life threatening or clinically significant uncontrolled systemic infection not related to AML.
•Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the Intensive Chemotherapy Study only.
•Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the Intensive Chemotherapy Study only.
•Known malabsorption syndrome or other condition that may significantly impair absorption of study medication in the investigator's judgment (eg, gastrectomy, lap band, Crohn's disease) and inability or unwillingness to swallow tablets or capsules.
•Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.
•Concurrent administration of herbal preparations.
•Major surgery or radiation within 4 weeks of starting study treatment.
•Documented or suspected hypersensitivity to any one of the following:
•For subjects assigned to intensive chemotherapy, documented or suspected hypersensitivity to cytarabine (not including drug fever or exanthema, including known cerebellar side effects) or daunorubicin.
•For subjects assigned to non intensive chemotherapy, documented or suspected hypersensitivity to azacitidine or mannitol.
•Known active drug or alcohol abuse.
•Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
•Pregnant females or breastfeeding female subjects.
•Known recent or active suicidal ideation or behavior.
•Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.

干预措施: Placebo (Drug)

结局指标

主要结局

Intensive Study: Overall Survival (OS)

时间窗: Baseline up to 25 months

OS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.

Non-intensive Study: Overall Survival (OS)

时间窗: Baseline up to 25 months

OS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.

次要结局

Intensive Study: Percentage of Participants Who Improved in Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Questionnaire(Post-baseline up to Week 8)
Non-intensive Study: Percentage of Participants Who Improved in Fatigue Score Measured by the MDASI-AML/MDS Questionnaire at Week 12(Post-baseline up to Week 12)
Intensive Study: Percentage of Participants With Complete Remission Including Negative Minimal Residual Disease (CRMRD-neg)(Day 1 up to maximum of 2 years)
Intensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS)(Day 1 up to maximum of 2 years)
Intensive Study: Percentage of Participants With Partial Remission (PR)(Day 1 up to maximum of 2 years)
Non-intensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS)(Day 1 up to maximum of 3 years)
Non-intensive Study: Percentage of Participants With Partial Remission (PR)(Day 1 up to maximum of 3 years)
Intensive Study: Percentage of Participants With Complete Remission Without Negative Minimal Residual Disease (CRMRD-neg)(Day 1 up to maximum of 2 years)
Non-intensive Study: Percentage of Participants With Complete Remission (CR) Including Negative Minimal Residual Disease (CRMRD-neg)(Day 1 up to maximum of 3 years)
Intensive Study: Duration of Response (DoRi)(From date of first achieving CRi or better to the date of relapse after CRi or better or death due to any cause (maximum up to 2 years))
Non-intensive Study: Duration of Response (DoRi) or (DoRh)(From date of first achieving CRi/CRh or better to the date of relapse/disease progression after CRi/CRh or better or death due to any cause (maximum up to 3 years))
Non-intensive Study: Percentage of Participants With Complete Remission Without Negative Minimal Residual Disease (CRMRD-neg)(Day 1 up to maximum of 3 years)
Intensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi)(Day 1 up to maximum of 2 years)
Non-intensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi)(Day 1 up to maximum of 3 years)
Intensive Study: Participants Global Impression of Change (PGIC)(Day 1 up to maximum of 2 years)
Non-intensive Study: Participants Global Impression of Change (PGIC)(Day 1 up to maximum of 3 years)
Intensive Study: Number of Participants With Adverse Events (AEs),Serious Adverse Events (SAEs) and According to Severity AEs Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 2 years)
Non-intensive Study: Number of Participants With Adverse Events (AEs),Serious Adverse Events (SAEs) and According to Severity AEs Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 3 years)
Intensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 2 years)
Non-intensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 3 years)
Intensive Study: Number of Participants With Shift From Baseline in Hematological Laboratory Abnormalities Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 2 years)
Non-intensive Study: Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh)(Day 1 up to maximum of 3 years)
Non-intensive Study: Time to Response(From the date of randomization to the first documentation of response (CRi/CRh or better) (maximum up to 3 years))
Intensive Study: Event-free Survival (EFS)(From the date of randomization to the date of TF, relapse from CR, or death from any cause, whichever comes first (maximum up to 2 years))
Intensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score(Day 1 up to maximum of 2 years)
Non-intensive Study: Event-free Survival (EFS)(From the date of randomization to the date of TF, relapse from CR, or death from any cause, whichever comes first (maximum up to 3 years))
Non-intensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score(Day 1 up to maximum of 3 years)
Intensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score(Day 1 up to maximum of 2 years)
Non-intensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score(Day 1 up to maximum of 3 years)
Intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS)(Day 1 up to maximum of 2 years)
Non-intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS)(Day 1 up to maximum of 3 years)
Intensive Study: Participants Global Impression of Symptoms (PGIS)(Day 1 up to maximum of 2 years)
Non-intensive Study: Participants Global Impression of Symptoms (PGIS)(Day 1 up to maximum of 3 years)
Non-intensive Study: Number of Participants With Shift From Baseline in Hematological Laboratory Abnormalities Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 3 years)
Intensive Study: Number of Participants With Shift From Baseline in Chemistry Laboratory Abnormalities Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 2 years)
Non-intensive Study: Number of Participants With Shift From Baseline in Chemistry Laboratory Abnormalities Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 3 years)
Intensive Study: Number of Participants With Shift From Baseline in Coagulation Laboratory Abnormalities Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 2 years)
Non-intensive Study: Number of Participants With Shift From Baseline in Coagulation Laboratory Abnormalities Graded by NCI CTCAE v.4.03(Day 1 up to maximum of 3 years)
Intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib(Induction, Day 10+/-1: pre-dose, 1, 4 hour (hr); Consolidation phase, Day 1: pre-dose, 1, 4 hr)
Non-intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib(Pre-dose: Cycle 1 Day 15 and Cycle 2 Day 1)
Intensive Study: Number of Participants With Shift From Baseline in Corrected QT (QTc) Interval(Day 1 up to maximum of 2 years)
Non-intensive Study: Number of Participants With Shift From Baseline in Corrected QT (QTc) Interval(Day 1 up to maximum of 3 years)

研究者

发起方

Pfizer

申办方类型

Industry

责任方

Sponsor

研究点 (149)

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