A Phase 1 Trial of the Hematopoietic Growth Factor CDX-301 (rhuFlt3L) in Healthy Volunteers

Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSC), early progenitor cells, immature thymocytes, and steady state dendritic cells and induces the proliferation, differentiation, development and mobilization of these cells in the bone marrow, peripheral blood, and lymphoid organs. Given its potential as a stem cell mobilizer and immunotherapeutic, the safety and biologic activity of recombinant human (rh) Flt3L were originally demonstrated in clinical studies conducted by Immunex Inc.  Development has recently been reinitiated with CDX-301, which is composed of the identical amino acid sequence and comparable biologic activity as the product first tested by Immunex.  A Phase 1 trial was initiated to assess the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301. Using a standard 3+3 dose-escalating design, subjects receive daily subcutaneous injection of CDX-301 at a dose level of 1, 3, 10, 25 or 75 mcg/kg x 5 days (Cohorts 1-5), 25 mcg/kg x 7 days (Cohort 6), or 25 mcg/kg x 10 days (Cohort 7), followed by 28-day observation.   30 healthy volunteers (HV) (67% male, median age = 34 years) have been enrolled.  All HV in Cohorts 1-6 have completed dosing; CDX-301 administration continues for Cohort 7.   In Cohort 5, one HV with a remote history of community acquired pneumonia was hospitalized with community acquired pneumonia which developed on study day 12; the event responded rapidly to antibiotic treatment and fully recovered within 2 weeks, but was considered a dose-limiting toxicity given the temporal association with CDX-301 administration. The cohort was expanded to a total of six HV. No additional infections or DLT have been reported to date. Transient Grade 1 lymphadenopathy has been reported for 6 HV across multiple dose levels. No anti-CDX-301 antibodies have been detected through end of study day 34 in Cohorts 1-5; testing for Cohorts 6-7 is ongoing. White blood cell count (WBC) and monocytes increased in all HV; peak levels were observed around Day 10 and generally returned to baseline by Day 34.

At doses above 3 mcg/kg, there was no clear dose response; mean maximum % change from baseline for Cohorts 3-6 = 99% (range: 43-224%) for WBC and 784% (range: 264-1400%) for monocytes. In-depth phenotypic and/or functional analysis of hematopoietic stem cells and dendritic cell subsets are planned. Data from this current Phase 1 trial are consistent with previous studies showing that rhFlt3L is well-tolerated and can safely and effectively mobilize hematopoietic cell populations. Data from this trial are expected to define the dosing regimen for planned trials of CDX-301 in allogeneic hematopoietic stem cell transplantation (HSCT) and immunotherapy.