Study design

This study is conducted under FDA IND 122657, registered in ClinicalTrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT02193191","term_id":"NCT02193191"}}NCT02193191, and approved by the Institutional Review Boards of Memorial Sloan Kettering, Weill Cornell Medical College and the New York Blood Center. The study design is a 3 + 3 dose escalation study with six levels of escalation: doses of 80, 160, 240, 320, 400, and 480 μg/kg. There are two primary endpoints: (i) efficacy, defined by the achievement of a HPC mobilization level of 30 CD34⁺ cells/μL; and (ii) safety, defined by the occurrence of serious adverse events (≥ grade 3) that are at least possibly plerixafor-related (including vaso-occlusive events).

At any dose level, the occurrence of at least one grade 3 serious adverse event results in the addition of three more patients to the initial three-patient dosing cohort. The occurrence of two grade 3 serious adverse events at a particular dose-level signifies that the maximal tolerated dose has been exceeded and that the previous dose-level is the maximum tolerated dose. The trial will be stopped upon the occurrence of one grade 4 or 5 serious adverse event at least possibly related to plerixafor. Patients are followed for adverse events for 1 month after administration of the plerixafor. This design provides the following probabilities of escalation based on the true chance of a dose-limiting toxicity at a specific dose level: True probability of toxicity 0.10 0.20 0.30 0.40 0.50 0.60 Probability of escalation: 0.91 0.71 0.49 0.31 0.17 0.08

For the efficacy endpoint, the dose escalation will continue to 480 μg/kg unless all patients at a preceding dose level achieve a peripheral blood CD34⁺ concentration of at least 30 cells/μL. In the present dose-escalation phase, no leukapheresis is performed. If and when the efficacy endpoint is safely reached, the study will proceed to a leukapheresis phase (including preclinical transduction and editing) in three patients.

Eligible subjects are adults with SS or Sβ⁰ disease, normal renal and liver function, hemoglobin concentration ≥6 g/dL, WBC count ≥3,000/μL, absolute neutrophil count (ANC) ≥1,500/μL, and platelet count of ≥150,000/μL. Eligible subjects are admitted to the Clinical Research Center at Weill Cornell Medical College. A single subcutaneous injection of plerixafor (Sanofi-Genzyme) is administered in the evening between 8–9 pm. The protocol calls for peripheral blood sampling at three time points (baseline, 0–2 h prior to plerixafor; peak between 6–12 h after the plerixafor dose; at the presumed return to baseline between 20–24 h after the dose): for reasons of feasibility and patient comfort issues, the peak sample was consistently drawn at a mean of 12 ± 1 h after plerixafor administration and the return to baseline sample at a mean of 20 ± 0.29 h after the dose. Since patients have pre-existing anemia, for reasons of safety no more than a total of 105 mL of blood is drawn at all three time points combined.