A Phase 1, Open Label, Dose Escalation, Dose Expansion, Multicenter Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of Oral AUR108 in Patients With Relapsed Advanced Lymphomas(ASHA-1)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 43
- 主要终点
- 1. First cycle Dose Limiting Toxicities (DLT)
研究概览
简要总结
An open-label, first-in-human, Phase 1 study in adult patients with relapsed advanced lymphomas will be done to assess AUR108 safety, tolerability, pharmacokinetics, pharmacodynamics, and optimal biological dose.
详细描述
This is a Phase I, Open Label, Dose-Escalation, First-in-Human study in adult patients with select relapsed advanced lymphomas. The safety and tolerability of oral AUR108 will be evaluated in patients with Non-Hodgkin lymphoma and Hodgkin lymphoma who do not have any available curative or life-prolonging treatment options and have exhausted all effective locally available therapies. The traditional 3+3 design for dose escalation will be used to evaluate the safety, pharmacokinetics/pharmacodynamics, and determine the Optimal Biological Dose of AUR108 as a single agent. The Optimal Biological Dose will be selected using a totality of safety, PK, and PD data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males or females ≥ 18 years of age
- •Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1
- •Acceptable bone marrow and organ function at screening as described below:
- •ANC ≥ 1000/μL (without WBC growth factor support)
- •Platelet count ≥ 75,000/μL without transfusion support
- •Hemoglobin ≥ 9 g/dL (Transfusion is allowed to achieve this Hb)
- •Total Bilirubin ≤ 1.5 x ULN; (Patients with known Gilbert's syndrome are allowed with a Total Bilirubin ≤ 2.5 x ULN)
- •AST (SGOT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases)
- •ALT (SGPT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases)
- •Creatinine clearance (CrCl) ≥ 30 mL/min (either measured or estimated by the Cockcroft-Gault formula). (Cockcroft-Gault formula for estimated creatinine clearance [eCrCl]: eCrCl = [140- Age] × Weight [kg] × [0.85 if Female] / [72 × serum creatinine (mg/dL)]).
- •Ability to swallow and retain oral medications
- •Histo-pathological diagnosis of a Non-Hodgkin lymphoma orHodgkin Lymphoma. Note: The lymphoma should be either in Stage III or IV according to Lugano classification (Cheson BD et al, 2014) at screening.
- •In the case of subjects who have lymphoma for which high-dose chemotherapy and autologous stem cell transplantation (HDASCT) is considered a standard curative therapy, eligibility for this study requires that the subject's disease has relapsed after HDASCT, that the subject is not eligible for HD-ASCT, or that the subject has refused HD-ASCT.
- •In the case of subjects who have lymphoma for which CAR-T therapy is considered a standard therapy, eligibility for this study requires that the subjects disease has relapsed after CAR-T, or that the subject has refused CAR-T, or that the CAR-T therapy is not accessible to the patient.
- •Evidence of measurable disease as per Lugano Criteria for Lymphoma (Cheson BD et al, 2014).
- •Standard curative measures do not exist, and patient must have exhausted all effective therapies, available locally.
- •At a minimum, the patients must have received at least 2 prior lines of systemic therapies. These systemic therapies could be either in the stage II, III or IV.
- •Any cancer patient with access to any effective therapy must not be enrolled.
排除标准
- •Systemic anti-cancer therapy, such as chemotherapy, or biological therapy, immunomodulatory drug therapy, received within the past 28 days or 5 half-lives, whichever is longer, from the Cycle 1 Day 1 of the study.
- •Note: Concomitant use of low dose prednisone (up to 10 mg/day) is allowed.
- •Presence of an acute or chronic toxicity resulting from prior anticancer treatment, with the exception of alopecia or nail changes, that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 5.
- •Definitive Radiotherapy within the last 21 days of Cycle 1 Day 1 (limited field palliative radiation is allowed and no restrictions during the screening period or during the trial).
- •Use of any investigational agent within 28 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day
- •Patients with cutaneous lymphomas, mycosis fungoides (MF) or Sézary syndrome (SS).
- •Primary CNS lymphoma
- •Known symptomatic or untreated or recently treated (≤ 6 months of screening) central nervous system (CNS) lymphoma. Patients with previously treated (> 6 months of screening) CNS lymphoma and are now stable and asymptomatic, from CNS perspective, are allowed
- •Patients with lymphoma that requires immediate cytoreductive therapy
- •Patients with lymphoma that requires immediate cytoreductive therapy
- •Patients on the drugs which are sensitive substrates of CYP2C8 and cannot be discontinued at least one week prior to Cycle 1 Day 1
- •Patients on the drugs which are sensitive substrates of either Poglycoprotein (P-gp) or breast cancer resistance protein (BCRP) and cannot be discontinued at least one week prior to Cycle 1 Day 1
- •Major surgery ≤ 28 days from Cycle 1 Day 1 (major surgery is defined as a procedure requiring general anesthesia)
- •Active infection requiring systemic therapy. Note: Prophylactic use of antibiotics is allowed. Any infection detected during screening period which is resolved adequately according to investigator before the Cycle 1 Day 1, is allowed.
- •Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
- •Known active or chronic hepatitis B (HbsAg +ve) or hepatitis C infection (HCV antibody +ve)
- •The patient who is expected to require any other form of antineoplastic therapy or targeted therapy while on study.
- •Uncontrolled congestive heart failure (New York Heart Association (NYHA) Class 2-4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, or transient ischemic attack, or pulmonary embolism within 3 months prior to Cycle 1 Day 1
- •Ongoing cardiac dysrhythmias requiring treatment of any grade or treatment of cardiac dysrhythmias in past 3 months, before Cycle 1 Day
- •QTc (Bazzett) interval >460 ms on ECG at screening and/or at Cycle 1 Day 1 pre-dose.
- •Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or significant gastritis, active bleeding diatheses, presence of any major medical illness (e.g. renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, or psychiatric illness/social situations or clinically significant laboratory / ECG abnormalities at screening, any or a combination of illnesses, which, in the opinion of the PI, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study
- •Current swab-positive or suspected (under investigation) Covid-19 infection or fever and other signs or symptoms suggestive of Covid-19 infection with recent contact of person(s) with confirmed Covid-19 infection, at screening or Cycle 1 Day
- •History of another primary malignancy within 5 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study.
- •Positive pregnancy test for women of child-bearing potential (WOCBP) at the screening or enrolment visit
- •Lactating women or WOCBP who are neither surgically sterilized nor willing to use reliable contraceptive methods (hormonal contraceptive, IUD, or any double combination of male or female condom, spermicidal gel, diaphragm, sponge, cervical cap).
研究组 & 干预措施
AUR108, 50mg to 300mg
Currently, planned dose levels are 50,90,150,220,300 mg will be administered in 3+/4- regimen.
干预措施: AUR108 (Drug)
结局指标
主要结局
1. First cycle Dose Limiting Toxicities (DLT)
时间窗: 28 Days
Assess dose limiliting toxicities of AUR108
Pharmacokinetics: Time to Maximum concentration (Tmax)
时间窗: Day 1 and Day 17
Tmax in hours
Pharmacokinetics: Area under the curve (AUC)
时间窗: Day 1 and Day 17
Area under the curve (AUC) of AUR108 in h\* ng/mL
Pharmacokinetics: Terminal elimination half-life
时间窗: Day 17
Terminal elimination half-life of AUR 108 in hours
Pharmacokinetics Maximum Concentration (Cmax)
时间窗: Day 1 and Day 17
Maximum Concentration of AUR108
Time to Maximum concentration (Tmax) administered under fasting/fed condition
时间窗: Day 8
Compare Tmax in fast and fed conditions
Safety of AUR108 as measured by the number of participants with treatment-related adverse events (AE) graded according to NCI CTCAE version 5.0
时间窗: Through study completion, an average of 1 year
Number of participants with TEAEs
Maximum concentration (Cmax) administered under fasting/fed condition
时间窗: Day 8
Compare in fast and fed conditions
Area under curve (AUC) administered under fasting/fed condition
时间窗: Day 8
Compare AUC in fast and fed conditions
次要结局
未报告次要终点