A Phase 1 Open Label, Multi-Center, Dose Escalation Study of Nilotinib (NLT) in Steroid Dependent / Refractory Chronic Graft-Versus-Host Disease (cGvHD)

We previously reported that the maximum tolerated dose (MTD) of NLT for cGvHD was 200 mg daily for 16 subjects treated according to a standard 3+3 dose escalation schema (Chen et al, Blood 2011 118: Abstract 1986).  We present new efficacy data and update prior safety and pharmacokinetic data in 28 subjects. 

Methods.  All subjects had extensive steroid dependent/refractory cGvHD previously treated with ≥ 2 agents.  Glucocorticoid (GC) refractory was defined as progressive cGVHD despite prednisone ³ 0.5 mg/kg/d for ≥ 1 month; steroid dependence was cGvHD requiring prednisone ≥0.25 mg/kg/d for ≥ 3 months.  GCs and two other immunosuppressants were allowed.  Prior imatinib use was allowed.  GCs were tapered as tolerated and other immunosuppressant dosing remained constant.  Safety was determined by observation of CTCAE v. 4.0 graded adverse events (AEs).  Trough plasma NLT concentrations were determined by LC/MS before the daytime day 8 dose.  Clinical activity of NLT was indicated by change in NIH composite skin (Δ ≥1) and Lee symptom skin scores (improvement Δ ≥13, worsening Δ ≥-20).

 Results.  Median (range) follow-up was 153 (19-581) days.  Median age (range) was 50.3 (24.5-76.4) years.  Mean time (range) to study enrollment from transplant was 3.8 (1.5-13.3) years and from cGvHD diagnosis 3.4 (0.3-12.6) years.  The table shows grade 2-3 AEs possibly or probably attributed to NLT.  So far no grade 4-5 AEs attributed to NLT have occurred.  Median trough concentration of NLT 1 week after drug initiation at the MTD (n=23) was 761 nM (range 120-2290 nM).  26 subjects were evaluable for response.  6 remain on drug.  20 were removed from the study for progressive disease (7), toxicity (7), withdrawal of consent (5), and progression of underlying malignancy (1).  Skin disease responses could be evaluated in 19 subjects.  NIH composite skin score was improved in 4, unchanged in 14, and worsened in 1.  Lee symptom skin score was improved in 6 and unchanged in 13.  Among the 7 subjects with progressive cGvHD, NIH composite or Lee symptom skin score was unchanged or worsened in 5, improved in 1, and unevaluable in 1.

Conclusions.  Skin improvement in some patients suggests that NLT 200 mg daily may have clinical activity.  Median trough concentrations that exceeded the IC50s for PDGFRA, DDR1, DDR2, ABL, and KIT but not NQO2 support this.  200 mg daily, however, is associated with significant toxicity.  Lower daily doses or alternate day dosing may continue to generate disease responses while improving tolerability and should be explored.

Adverse Event	Grade 2 (n=28)	Grade 3 (n=28)
Arterial injury	1
Decreased joint flexion	1	1
Dehydration	1
LFT elevation	2	1
Hyponatremia		1
Hypophosphatemia (1 Ф)	6	3
Increased lipase (3 Ф)	2	2
Influenza B		1
Muscle cramping	1	1
Neutropenia (afebrile)	1	1
Pneumocystis carinii pneumonia (1 Ф)		1
Prolonged QTc	1
Shingles	1	1
Suspected fungal pneumonia	1
URI		1
Worsening Fatigue	2
Ф DLT