NCT03465540终止1 期
A Phase 1 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Amgen
- 入组人数
- 24
- 试验地点
- 21
- 主要终点
- Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
研究概览
简要总结
Evaluate the safety and tolerability of AMG 397. Estimate the maximum tolerated doses (MTDs) and/or biologically active doses.
详细描述
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study evaluating AMG 397 administered orally once weekly, as part of a 28-day treatment cycle in adult subjects with selected relapsed or refractory hematological malignancies
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject has provided informed consent prior to initiation of any study-specific activities/procedures
- •Age ≥ 18 years old
- •Pathologically-documented, definitively-diagnosed relapsed or refractory multiple myeloma (MM), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML) and is intolerant to, or considered ineligible for available therapies known to provide clinical benefit
- •MM subjects only: Measurable disease per the International Myeloma Working Group (IMWG) response criteria (assessed within 21 days prior to enrollment), as indicated by one or more of the following: cytogenic risk factor: 1q21 amplification/gain, serum M-protein ≥ 0.5 g/dL, Urine M-protein ≥ 200 mg/24 hours. For Subjects who do not meet 1 of the 2 prior criteria: Serum Free Light Chain (sFLC) ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal sFLC ratio (< 0.26 or > 1.65) as per the IMWG response criteria
- •MM subjects only: Hematological function, as follows without transfusion or growth factor support within 2 weeks prior to study day 1: absolute neutrophil count ≥ 1.0 X 109/L, hemoglobin > 8 g/dL and platelet count ≥ 75 X 109/L
- •AML subjects only: Pathologically confirmed diagnosis of AML as defined by the World Health Organisation (WHO) Classification, more than 5% blasts in bone marrow and persisting or recurring following one or more treatment courses
- •MDS subjects only: pathologically confirmed diagnosis of MDS as defined by the WHO Classification, intermediate and high risk MDS and intolerant or refractory to HMA treatment
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- •Life expectancy of > 3 months, based on the opinion of the investigator
- •Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption.
- •Hepatic function, as follows:
- •aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
- •total bilirubin (TBL) < 1.5 X ULN (except subjects with Gilbert's syndrome)
- •Cardiac function, as follows:
- •Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion as determined by echocardiogram or multigated acquisition (MUGA) scan
- •no ECG findings representing a recent cardiac injury within 6 months before enrollment
- •Renal function as follows:
- •Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault [(140 - Age) × Mass (kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female
排除标准
- •Disease Related
- •Previously received an allogeneic stem cell transplant within 6 months of study day 1 OR having signs or symptoms of acute or chronic graft-versus-host disease
- •Autologous stem cell transplant < 90 days before enrollment
- •Candidates for stem cell transplant should have failed or are not considered eligible for either allogeneic and autologous transplant
- •Other Medical Conditions
- •History of other malignancy except:
- •Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated cervical carcinoma in situ without evidence of disease
- •Adequately treated breast ductal carcinoma in situ without evidence of disease
- •Prostatic intraepithelial neoplasia without evidence of prostate cancer
- •Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
- •Myocardial infarction within 6 months before enrollment
- •Symptomatic congestive heart failure (New York Heart Association > Class II)
- •History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 6 months before enrollment
- •Uncontrollable active infection requiring intravenous anti-infective treatments within 1 week before enrollment
- •Known positive results for human immunodeficiency virus (HIV)
- •Active hepatitis B and C based on the following results: Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic, hepatitis B or recent acute hepatitis B), Negative HBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B. Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C
- •Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1, or to levels dictated in the eligibility criteria with the exception of grade 2peripheral neuropathy, alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for > 4 weeks prior to study day 1 may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor)
- •Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent or procedures) within 14 days of day 1
- •Prior systemic radiation therapy must have been completed at least 28 days before study day
- •Prior focal radiotherapy completed at 14 days before study day 1
- •Females of reproductive potential who are unwilling to practice acceptable methods of highly effective contraception while on study through 8 months after receiving the last dose of study drug. Males who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use a condom with or without spermicide while on study through 5 months after receiving the last dose of study drug if sexually active with a female of childbearing potential
- •Females who are lactating/breastfeeding or who plan to breastfeed while on study through 8 months after receiving the last dose of study drug
- •Females with a positive pregnancy test or planning to become pregnant while on study through 8 months after receiving the last dose of study drug
- •Males who are unwilling to abstain from sperm donation while on study through 8 months after receiving the last dose of study drug
- •History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
- •Use of any over-the-counter or prescription medications within 14 days or 5 half-lives (whichever is longer), prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
- •Use of herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the subject within 14 days prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
- •Use of any known inhibitors of P-gp within 14 days or 5 half-lives (whichever is longer) or grapefruit juice or grapefruit containing products within 7 days prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
- •Use of known CYP3A4 sensitive substrates, (with a narrow therapeutic window), within 14 days or 5 half-lives (whichever is longer) of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
- •Use of known P-gp substrates (with a narrow therapeutic window) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
- •Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, long term follow-up) to the best of the subject and investigator's knowledge
- •Known sensitivity to any of the products or component to be administered during dosing
- •MM subjects with any of the following criteria are excluded:
- •Multiple myeloma with IgM subtype
- •POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- •Existing plasma cell leukemia
- •Waldenstrom's macroglobulinemia
- •Amyloidosis
- •AML subjects with the following criteria are excluded:
- •Circulating white blood cells > 25,000/μl. Hydroxyurea to control peripheral blood leukemic cell counts, within 24 hours of study day 1 is permitted
- •Promyelocytic leukemia
- •AML/MDS subjects fit for intensive salvage therapy
- •Subjects with elevated cardiac troponin above the manufacturer's 99th percentile upper reference limit for ADVIA Centaur XP assay at screening performed by the central laboratory (Covance)
- •Subjects with evidence of recent cardiac injury at screening based on creatine kinase-muscle/brain (CK-MB), N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP), and ECG assessments at screening
- •Subjects with MDS that are eligible for hematopoietic stem cell transplant (HSCT)
研究组 & 干预措施
Part 1A: AMG 397 Dose Escalation
Experimental
This arm includes subjects with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL).
干预措施: AMG 397 (Drug)
Part 1B: AMG 397 Dose Escalation
Experimental
This arm includes subjects with acute myeloid leukemia (AML).
干预措施: AMG 397 (Drug)
Part 2A: AMG 397 Monotherapy
Experimental
This arm includes subjects with AML or myelodysplastic syndrome (MDS).
干预措施: AMG 397 (Drug)
Part 2B: AMG 397 Monotherapy
Experimental
This arm includes subjects with AML in Japan only.
干预措施: AMG 397 (Drug)
Part 2C: AMG 397 Monotherapy
Experimental
This arm includes subjects with MM.
干预措施: AMG 397 (Drug)
Part 3A: AMG 397 + Azacitidine Combotherapy
Experimental
This arm includes subjects MDS.
干预措施: AMG 397 (Drug)
Part 3A: AMG 397 + Azacitidine Combotherapy
Experimental
This arm includes subjects MDS.
干预措施: Azacitidine (Drug)
Part 3B: AMG 397+ Azacitidine Combotherapy
Experimental
This arm includes subjects AML.
干预措施: AMG 397 (Drug)
Part 3B: AMG 397+ Azacitidine Combotherapy
Experimental
This arm includes subjects AML.
干预措施: Azacitidine (Drug)
Part 3C: AMG 397+ Dexamethasone Combotherapy
Experimental
This arm includes subjects MM.
干预措施: AMG 397 (Drug)
Part 3C: AMG 397+ Dexamethasone Combotherapy
Experimental
This arm includes subjects MM.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
时间窗: 28 days
DLTs were defined as specific adverse events (AEs) that occurred in a participant during the DLT evaluation period (Day 1 to Day 28), that the investigator assessed as related to AMG 397. The grading and severity of AEs were based on the guidelines provided in the common terminology criteria for adverse events (CTCAE) version 4.03.
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
时间窗: Up to 30 days after last dose (Maximum time on treatment was 18 weeks for part 1a and 13 weeks for part 1b)
A TEAE was defined as any AE starting on or after the first dose of investigational product. Any clinically significant changes in vital signs, physical examinations, electrocardiogram (ECGs) and clinical laboratory test results were recorded as AEs. The grading and severity of adverse events were based on the guidelines provided in the CTCAE version 4.03. Treatment-related TEAEs were any events that the investigator assessed as related to AMG 397.
次要结局
- Overall Response Rate (ORR) for Participants With Multiple Myeloma (MM)(Up to end of study (a maximum of 48 weeks))
- Overall Response Rate (ORR) for Participants With Non-Hodgkin's Lymphoma (NHL)(Up to end of study (a maximum of 48 weeks))
- Overall Response Rate (ORR) for Participants With Acute Myeloid Leukemia (AML)(Up to end of study (a maximum of 48 weeks))
- Progression-free Survival (PFS)(Up to end of study (a maximum of 48 weeks))
- Overall Survival (OS)(Up to end of study (a maximum of 48 weeks))
- Time to Response (TTR)(Up to end of study (a maximum of 48 weeks))
- Duration of Response (DOR)(Up to end of study (a maximum of 48 weeks))
- Maximum Observed Concentration (Cmax) of AMG 397(Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2)
- Time to Maximum Observed Concentration (Tmax) for AMG 397(Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2)
- Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397(Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22)
- Clearance (CL) of AMG 397(Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22)
- Half-life (t1/2) of AMG 397(Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22)
研究者
研究点 (21)
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