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

Abstract 4124

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, but development had been halted. CDX-301 is a soluble, rhFlt3L composed of the identical amino acid sequence and comparable biologic activity as the Immunex product. 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, 18 healthy volunteers (HV) (51% male, median age = 32 years) received 5 daily subcutaneous injections of CDX-301 (at a dose of 1, 3, 10, 25 or 75 mcg/kg) followed by 28-day observation. All HV completed dosing and CDX-301 was well tolerated. Dose-escalation proceeded through the 25 mcg/kg dose level with no DLT (n=3 in each cohort). In the 75 mcg/kg cohort, one HV with a remote history of community acquired pneumonia developed community acquired pneumonia 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, and no additional infections or DLT were reported. Transient Grade 1 lymphadenopathy was observed in 3 HV across multiple dose levels. No anti-CDX-301 antibodies were detected through end of study day 34 in any HV. 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 the HV receiving 10 – 75 mcg/kg = 111% (range: 55–224%) for WBC and 800% (range: 450–1167%) for monocytes.

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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 can safely and effectively mobilize hematopoietic cell populations. Two additional cohorts will receive extended dosing (25 mcg/kg dose; 7 & 10 day durations) to further define an optimal dosing regimen for planned trials of CDX-301 in allogeneic hematopoietic stem cell transplantation (HSCT) and immunotherapy.