A Phase 1/2, Open-Label, Dose Escalating Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AB1 in Adult Patients with Sickle Cell Disease (SCD)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Nirmish Shah
- 入组人数
- 16
- 试验地点
- 3
- 主要终点
- Number of ≥Grade 2 study related adverse events as measured by patient report/medical record
研究概览
简要总结
This will be an open-label, dose escalating study with a starting dose of 2mg. Up to 6 additional cohorts will be enrolled at subsequently higher doses of 4mg, 8mg, 10mg, 12mg, 16mg, and 32mg. In each dose escalation cohort, each dose will be taken orally, once daily, for 8 weeks.
详细描述
This will be an open-label, dose escalating study with a starting dose of 2mg. Up to 4 additional cohorts will be enrolled at subsequently higher doses of 4mg, 8mg, 16mg, and 32mg.
- Cohort 1 - Two (2) patients will be enrolled at the 2mg dose level for 8 weeks of treatment. After both patients have received at least 4 weeks of treatment, if there are no adverse events ≥Grade 2 that are related (possibly, probably, or definitely) to the study drug, then the study will proceed to the next dose level. Note that if ≥Grade 2 toxicity is seen at this dose level, the study drug regimen may be modified (eg, twice or thrice weekly versus daily dosing).
- Cohort 2 - Two (2) patients will be enrolled at the 4mg dose level for 8 weeks of treatment. After both patients have received at least 4 weeks of treatment, if there are no adverse events ≥Grade 2 that are related to the study drug, then the study will proceed to the next dose level.
- Cohort 3 - Three (3) patients will be enrolled at the 8mg dose level for 8 weeks of treatment. After all patients have received at least 4 weeks of treatment, if <2 patients experience a related adverse event ≥Grade 2, then the study will proceed to the next dose level. (If ≥2 patients experience a related adverse event ≥Grade 2, the previous cohort will be expanded.)
- Cohort 4 - Three (3) patients will be enrolled at the 10mg dose level for 8 weeks of treatment. After all patients have received at least 4 weeks of treatment, if <2 patients experience a related adverse event ≥Grade 2, then the study will proceed to the next dose level. (If ≥2 patients experience a related adverse event ≥Grade 2, the previous cohort will be expanded.)
- Cohort 5 - Three (3) patients will be enrolled at the 12mg dose level for 8 weeks of treatment. After all patients have received at least 4 weeks of treatment, if <2 patients experience a related adverse event ≥Grade 2, then the study will proceed to the next dose level. (If ≥2 patients experience a related adverse event ≥Grade 2, the previous cohort will be expanded.)
- Cohort 6 - Three (3) patients will be enrolled at the 16mg dose level for 8 weeks of treatment. After all patients have received at least 4 weeks of treatment, if <2 patients experience a related adverse event ≥Grade 2, then the study will proceed to the next and final dose level. (If ≥2 patients experience a related adverse event ≥Grade 2, the previous cohort will be expanded.)
- Cohort 7 - Three (3) patients will be enrolled at the 32mg dose level for 8 weeks of treatment.
- An additional cohort may be explored at the 24mg dose level if deemed appropriate based on safety and activity parameters.
If there are any adverse events Grade ≥2 that are related (possibly, probably, or definitely) to study drug, at the 4mg cohort or in ≥2 patients in any subsequent cohort, the dose may be reduced to the previous cohort and an additional 3-6 patients (total of up to 9) may be enrolled into that cohort. Additionally, if Hbf levels increase >15% (expressed as a percentage of total Hb) in any cohort, the cohort can be expanded to an additional 3 to 6 patients as well as continue to the next cohort if safety parameters have been met. In the expansion cohort, patients will receive study drug treatment for an additional 4 weeks (total of 12 weeks)..
Approximately 6 to 39 patients may be enrolled for the entire study. Patients are eligible to enroll in a higher cohort of the study after a minimum of one-month washout from AB1 dosing, if their HbF levels return to baseline (<15%) and the investigator deems the patient eligible.
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 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written, informed consent
- •Age 18 to 45 years of age, inclusive at screening
- •Confirmed SS or S-b0-thalassemia SCD
- •Sickle crisis rate of 2-10 within the past year with no crisis in the last 28 days
- •HbF <8.6% of total Hb at screening
- •Regular compliance with comprehensive care and previous therapy -
排除标准
- •Experienced severe sepsis or septic shock within the previous 12 weeks
- •Febrile illness in the 1 week prior to baseline visit
- •Acute complications due to SCD (i.e., hospitalization, acute pain, or acute chest syndrome) in the 28 days prior to screening visit
- •Plans for hospitalization, surgery, or other major procedures during the duration of the study or between screening and baseline
- •ALT ≥2X the upper limit of normal or albumin <2.0 mg/dL or direct (conjugated) bilirubin ≥ 1.5 mg/dl*
- •Serum creatinine >2.9 mg/dL and calculated creatinine clearance <30 mL/min# *
- •Platelet count >800 x 109/L OR <150 x 109/L*
- •Absolute neutrophil count <1.5 x 109/L*
- •Currently pregnant or breastfeeding
- •Female of active childbearing potential$ who is unwilling or unable to adhere to the contraception requirements specified in the protocol
- •Male with female partner(s) of childbearing potential$ who is unwilling or unable to adhere to the contraception requirements specified in the protocol
- •Altered mental status or recurrent seizures requiring anti-seizure medications
- •Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such severity that death within 24 weeks is likely
- •Concurrent diagnosis of malignancy including MDS, leukemia, or an abnormal karyotype
- •Known Vitamin-B12, folate, or iron deficiency
- •New York Heart Association (NYHA) class III/IV status
- •Eastern Co-operative Oncology Group (ECOG) performance status ≥3
- •Participant is on chronic transfusion therapy (e.g., for history of TIA or stroke) and medically contraindicated to discontinue transfusions (unless multiple allo-antibodies prevent the patient from getting transfusions as scheduled)
- •Blood transfusion in the 28 days prior to screening visit or between screening and baseline visits
- •Known history of illicit drug or alcohol abuse within the past 12 months.
- •Current treatment with Oxbryta or Adakveo (must be off therapy for 30 days for Oxbryta with no plans to restart and off therapy for 3 months for Adakveo with no plans to restart)
- •Other experimental or investigational drug therapy in the past 28 days -
研究组 & 干预措施
AB1
AB1 is the investigational product in this study taken orally, once daily, for 8 weeks. This will be an open-label, dose escalating study with a starting dose of 2mg. Up to 6 additional cohorts will be enrolled at subsequently higher doses of 4mg, 8mg, 10 mg, 12 mg, 16mg, and 32mg.
干预措施: AB1 (Drug)
结局指标
主要结局
Number of ≥Grade 2 study related adverse events as measured by patient report/medical record
时间窗: From the time of consent up to 12 months
Adverse events that cause enough discomfort to interfere with usual daily activity; may warrant therapeutic intervention
Number of adverse events/serious adverse events as measured by patient report/medical records
时间窗: From the time of consent up to 12 months
次要结局
- Change in dose normalized AUC o-inf as measured by blood test(Baseline, week4, week8, week10)
- Change in CL as measured by blood test(Baseline, week4, week8, week10)
- Change in Vz as measured by blood test(Baseline, week4, week8, week10)
- Change in tmax as measured by blood test(Baseline, week4, week8, week10)
- Change in Vss as measured by blood test(Baseline, week4, week8, week10)
- Change in Cmax as measured by blood test(Baseline, week4, week8, week10)
- Change in t1/2 as measured by blood test(Baseline, week4, week8, week10)
- Change in AUC o-t as measured by blood test(Baseline, week4, week8, week10)
- Change in percentage of total percentage of total hemoglobin (HB) as measured by HPLC(Screening, baseline, week2,week4, week6, week8, week10, week12)
- Change in percentage of F-cells measured by flow cytometry(Screening, baseline, week2,week4, week6, week8, week10, week12)
- Change in percent reticulocytes as measured by blood tests(Screening, baseline, week2,week4, week6, week8, week10, week12)
研究者
Nirmish Shah
Associate Professor of Medicine
Duke University