AB1 in Adult Patients With Sickle Cell Disease (SCD)
Study Details
Study Description
Brief Summary
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. Each dose will be taken orally, once daily, for 8 weeks.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
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.
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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 1 that are related (possibly, probably, or definitely) to the study drug, then the study will proceed to the next dose level.
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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 1 that are related to the study drug, then the study will proceed to the next dose level.
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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 1, then the study will proceed to the next dose level.
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Cohort 4 - 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 1, then the study will proceed to the next and final dose level.
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Cohort 5 - Three (3) patients will be enrolled at the 32mg dose level for 8 weeks of treatment.
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Additional cohorts may be explored at 12 and 24mg dose levels if deemed appropriate based on safety and activity parameters.
If there are any adverse events >Grade 1 that are related (possibly, probably, or definitely) to study drug, at the 4mg cohort or >2 patients in any subsequent cohort, the dose may be decreased to that for the previous cohort and an additional 3 patients (up to a total of 5 or 6) may be enrolled into that previous cohort. Additionally, if HbF levels, as a percent of total Hb, increase to >15% in any cohort, the cohort can be expanded by an additional 3 patients, as well as continuing to the next cohort if safety parameters have been met.
Approximately 6 to 30 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 (<8.6%) and the investigator deems the patient eligible.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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 with additional cohorts enrolled at subsequently higher doses of 4mg, 8mg, 16mg, and 32mg. |
Drug: AB1
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. Each dose will be taken orally, once daily, for 8 weeks
|
Outcome Measures
Primary Outcome Measures
- Number of adverse events/serious adverse events as measured by patient report/medical records [From the time of consent up to 12 months]
- Number of ≥Grade 2 study related adverse events as measured by patient report/medical record [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
Secondary Outcome Measures
- Change in Cmax as measured by blood test [Baseline, week4, week8, week10]
- Change in tmax 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 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 Vss 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Written, informed consent
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Age 18 to 45 years of age, inclusive at screening
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Confirmed SS or S-b0-thalassemia SCD
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Sickle crisis rate of 2-10 within the past year with no crisis in the last 28 days
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HbF <8.6% of total Hb at screening
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Regular compliance with comprehensive care and previous therapy -
Exclusion Criteria:
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Experienced severe sepsis or septic shock within the previous 12 weeks
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Febrile illness in the 1 week prior to baseline visit
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Acute complications due to SCD (i.e., hospitalization, acute pain, or acute chest syndrome) in the 28 days prior to screening visit
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Plans for hospitalization, surgery, or other major procedures during the duration of the study or between screening and baseline
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ALT ≥2X the upper limit of normal or albumin <2.0 mg/dL or direct (conjugated) bilirubin ≥ 1.5 mg/dl*
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Serum creatinine >2.9 mg/dL and calculated creatinine clearance <30 mL/min# *
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Platelet count >800 x 109/L OR <150 x 109/L*
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Absolute neutrophil count <1.5 x 109/L*
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Currently pregnant or breastfeeding
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Female of active childbearing potential$ who is unwilling or unable to adhere to the contraception requirements specified in the protocol
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Male with female partner(s) of childbearing potential$ who is unwilling or unable to adhere to the contraception requirements specified in the protocol
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Altered mental status or recurrent seizures requiring anti-seizure medications
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Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such severity that death within 24 weeks is likely
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Concurrent diagnosis of malignancy including MDS, leukemia, or an abnormal karyotype
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Known Vitamin-B12, folate, or iron deficiency
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New York Heart Association (NYHA) class III/IV status
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Eastern Co-operative Oncology Group (ECOG) performance status ≥3
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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)
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Blood transfusion in the 28 days prior to screening visit or between screening and baseline visits
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Known history of illicit drug or alcohol abuse within the past 12 months.
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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)
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Other experimental or investigational drug therapy in the past 28 days -
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
Sponsors and Collaborators
- Nirmish Shah
Investigators
- Principal Investigator: Nirmish Shah, MD, Duke University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Pro00110179