Stromal cell-derived factor-1 (SDF-1) is a well known key signaling molecule in the proliferation, homing, engraftment and expansion of hematopoietic stem cells and leukocytes. CTCE-0214, a peptide produced by rational drug design, is an analog of SDF-1 and agonist of the SDF-1 receptor, CXCR4. In vitro and in vivo models have shown that CTCE-0214 mobilized blood and progenitor cells and enhanced the survival and expansion of cord blood cells (

Letters in Drug Design and Discovery.
1
:
126
,
2004
;
Exp Hematol.
32
:
470
,
2004
;
Exp Hematol.
32
:
300
,
2004
; Stem Cells. In press). In this first phase I clinical trial of CTCE-0214, the safety and tolerability of single doses of CTCE-0214 given subcutaneously to healthy subjects as well as the pharmacokinetic profile and the pharmacodynamic effects were studied. The randomized, double-blinded, placebo-controlled dose-escalation trial enrolled 24 subjects in six dose-escalation groups. Four healthy human subjects in each cohort received either CTCE-0214 or Placebo, randomized in a 3:1 ratio. The starting dose for CTCE-0214 was 0.2 mg/kg. Successive dose cohorts received 0.5 mg/kg, 0.8 mg/kg, 1.5 mg/kg, 2.0 mg/kg, and 3.0 mg/kg. CTCE-0214 was shown to be safe with no serious adverse events reported in any of the dose levels studied. The most common drug related adverse events were injection site pain and erythema which were transient and resolved without intervention. The severity of injection site pain appeared to have an association with the overall quantity of study drug administered. Moderate or severe pain was reported only in subjects who received at least 80 mg of CTCE-0214 per syringe. Dilution across more than one syringe appeared to be effective in reducing injection site pain. Pharmacokinetic analysis of CTCE-0214 plasma concentrations showed that Tmax was reached at 0.25 hours post-administration for all CTCE-0214 treated cohorts. The apparent terminal elimination half-life (t1/2) values were estimated to be 0.41 to 0.32 hours. CTCE-0214 administration was associated with significant dose-dependent increases in total white blood cell and neutrophil counts in treated subjects, peaking at around 6 hours post-injection. In the 3.0 mg/kg arm, the mean difference in neutrophil count from baseline was more than three times the corresponding figure in the Placebo arm. The same trend was apparent in the 2.0 and 1.5 mg/kg arms with a greater than two times and two times increases, respectively. These results suggest that SDF-1 agonists may potentially be used in patients with low neutrophil count receiving chemotherapy with or without the use of G-CSF. The potential for CTCE-0214 to mobilize neutrophils and other blood cells merits serious consideration.

Topics:
agonists, neutrophils, stromal cell-derived factor 1, subcutaneous injections, pain, injection site, adverse event, cxcr4 receptors, syringes, chemotherapy regimen

Author notes

Corresponding author

2005, The American Society of Hematology
2005
Sign in via your Institution