Phase I results of the selective JAK1 inhibitor itacitinib in patients with aGvHD

After allogeneic-hematopoietic stem cell transplantation (allo-HSCT), 50–70% of patients develop acute graft-versus-host disease (aGvHD), which accounts for approximately 10% of non-relapse mortality (NRM). First-line treatment for aGvHD often involves corticosteroids; however, corticosteroid-refractory aGvHD (SR-aGvHD) can develop. Preclinical studies have demonstrated that the Janus kinase (JAK) pathway is involved in the pathogenesis of aGvHD as JAK1/2 inhibition prevents the production of various cytokines, and consequently, the differentiation, proliferation, and trafficking of T cells.¹

Ruxolitinib, an oral selective JAK1/2 inhibitor, is already approved by the U.S. Food and Drug Administration (FDA) for the treatment of SR-aGvHD. However, newer preclinical studies have shown that specific targeting of JAK1 may abrogate the cytokine signaling involved in GvHD pathogenesis, without inducing cytopenias that are caused by the co-inhibition of JAK2 signaling. As such, itacitinib, a selective JAK1 inhibitor that has shown preclinical activity in aGvHD models, was investigated in an open-label, phase I trial.¹

Mark A. Schroeder from the Washington University School of Medicine, St. Louis, US, and colleagues evaluated the safety, efficacy, and pharmacokinetics (PK) of itacitinib in combination with corticosteroids in patients with treatment-naïve or SR-aGvHD. The results were recently published in Blood Advances.¹

Study design and patient characteristics^1,2

• This was an open-label, parallel-cohort, multicenter, phase I trial in adult patients who had received allo-HSCT from any source who developed Grade IIB to IVD aGvHD
• In total, 29 patients were randomized 1:1 to receive corticosteroids (2 mg/kg daily methylprednisolone or prednisone equivalent) plus oral itacitinib 200 mg (n = 14) or 300 mg (n = 15) once daily. Patients were stratified as treatment-naïve or steroid-refractory based on prior GvHD treatment
• Primary endpoints: safety and tolerability
• Secondary endpoints: overall response rate (ORR; defined as the proportion of patients with a complete response [CR], very good partial response [VGPR], or partial response [PR]) at Day 28, and population PK parameters
• Exploratory endpoints: immunophenotyping and biomarker analyses
• Patient characteristics can be seen in Table 1

Table 1. Patients characteristics¹

CIBMTR, Center for International Blood and Marrow Transplant Research; ECOG PS, Eastern Cooperative Oncology Group performance status; GI, gastrointestinal; GvHD, graft-versus-host disease
Characteristic	Patients (N = 29)
Age, median (range), years	51 (18–71)
Sex, male/female, %	69/31
Race, %
White	82.8
African American	6.9
Asian	6.9
Other	3.4
ECOG PS, %
0	6.9
1	44.8
2	44.8
3	3.4
GvHD organ involvement, %
Lower GI tract	58.6
Upper GI tract	31.0
Skin	44.8
Liver	17.2
Isolated skin	20.7
Skin + upper GI	6.9
> 1 organ involved	89.7
≥ 2 organs involved	48.3
GvHD Minnesota grade, %
II–IV	96.6
III/IV	62.1
GvHD CIBMTR grade, %
B–D	96.6
C/D	58.6

• Most patients had Grade III (55.2%) or Grade II (34.5%) aGvHD per Minnesota grading criteria, and Grade C (48.3%) or B (37.9%) per Center for International Blood and Marrow Transplant Research (CIBMTR) criteria
• Organ involvement was primarily in the lower gastrointestinal (GI) tract (58.6%), followed by skin (44.8%) and upper GI tract (31.0%)
• The median treatment duration was 76 days (range, 5–291) and 61 days (range, 5–817) for the 200 mg and 300 mg dose groups, respectively

Results¹

Safety

• The most common reasons for treatment discontinuation were adverse events (n = 8 in the 200 mg group, and n = 7 in the 300 mg group) and physician decision (n = 3 in the 200 mg group, and n = 5 in the 300 mg group)
• One dose-limiting toxicity of Grade 3 thrombocytopenia attributed to GvHD progression, was reported in the 300 mg dose group, however, the patient had preexisting thrombocytopenia
• The most common non-hematological treatment-emergent adverse event (TEAE) was diarrhea (48.3%, n = 14), with Grade 3/4 diarrhea reported in four patients in the 200 mg group, and two patients in the 300 mg group (Table 2)
• The most common hematological TEAE was anemia (37.9%, n = 11) followed by decreased platelet count (27.6%, n = 8), and thrombocytopenia (24.1%, n = 7) (Table 2)

Table 2. Hematological and non-hematological TEAEs¹

TEAE, treatment-emergent adverse event *Occurring in > five patients †Including patients with GI GvHD ‡Thrombocytopenia and decreased platelet count were mutually exclusive in this data set. Decreased platelet count was chosen in cases of laboratory decreases; thrombocytopenia was chosen as a clinical diagnosis.
Itacitinib dose	200 mg (n = 14)		300 mg (n = 15)
TEAE*	Grade 3/4	All grades	Grade 3/4	All grades
Non-hematological, %
Diarrhea†	28.6	57.1	13.3	40.0
Peripheral edema	0.0	28.6	6.7	60.0
Abdominal pain	14.3	42.9	6.7	33.3
Hypokalemia	28.6	42.9	20.0	33.3
Hyperglycemia	21.4	42.9	26.7	26.7
Fatigue	28.6	28.6	0.0	33.3
Decreased appetite	14.3	21.4	6.7	33.3
Tachycardia	14.3	42.9	0.0	13.3
Headache	0.0	35.7	0.0	13.3
Hypoalbuminemia	21.4	28.6	6.7	20.0
Hypophosphatemia	21.4	28.6	13.3	20.0
Nausea	0.0	35.7	6.7	13.3
Vomiting	0.0	35.7	6.7	13.3
Arthralgia	0.0	0.0	0.0	40.0
Fall	0.0	28.6	0.0	13.3
Hypertension	0.0	7.1	26.7	33.3
Hypogammaglobulinemia	0.0	28.6	0.0	13.3
Edema	7.1	21.4	0.0	20.0
Pyrexia	0.0	28.6	0.0	13.3
Hematological‡, %
Anemia	35.7	35.7	33.3	40.0
Decreased platelet count	14.3	14.3	40.0	40.0
Thrombocytopenia	14.3	21.4	20.0	26.7

• Seven patients (n = 4 in the 200 mg group; n = 3 in the 300 mg group) discontinued itacitinib because of TEAEs deemed related to itacitinib by the investigator
• Fatal adverse events were reported in nine patients, but none seemed related to itacitinib

Efficacy

• The ORR on Day 28 was 78.6% and 66.7% in the 200 mg and 300 mg dose groups, respectively
• At Day 28 the ORR was 75.0% for patients with treatment-naïve aGvHD and 70.6% in those with SR-aGvHD
• The NRM rate for all patients was 48.3% and was similar to the 200 mg (50%) and 300 mg (46.7%) dose groups separately
• NRM rate was 33% for patients with treatment-naïve aGvHD and 58.8% for patients with SR-aGvHD
• By day 56, all patients receiving itacitinib either discontinued corticosteroid treatment or decreased the corticosteroid dose

PK

• Itacitinib plasma concentrations across the two dose groups approached the ex vivo half-maximal inhibitory concentration for the inhibition of interleukin-6-induced phosphorylation of the signal transducer and activator of transcription
• The median time to maximum concentration (C_max) occurred 2–4 hours after itacitinib treatment
• A large overlap in steady-state PK exposures was observed between the two itacitinib doses (n = 24)

Biomarker and immunophenotyping analysis

• Plasma samples from 27 patients were available for biomarker analysis, including 19 responders (CR, VGPR, PR) and eight non-responders (mixed response, progressive disease/death)
• Mean baseline levels for tumor necrosis factor receptor 1 were significantly higher in non-responders compared to responders (3.8 vs6 ng/mL; p = 0.037)
• Itacitinib treatment was associated with decreased levels of markers for T-cell and regulatory T-cell activation. The total T-cell levels did not differ upon treatment
• CR to itacitinib was associated with elevated levels of natural killer (NK) cells, reduced levels of myeloid-derived suppressor cells (MDSC), and an NK:MDSC ratio of > 0.31

Conclusions

• Itacitinib was well tolerated and demonstrated preliminary efficacy in patients with steroid- naïve or SR-aGvHD
• TEAEs were consistent with those reported in patients with aGvHD and those in patients with myelofibrosis treated with itacitinib
• For future itacitinib studies, the 200 mg dose will be used for patients with aGvHD due to the similar efficacy and PK profiles observed across the doses, and due to the increased incidence of hematological adverse events reported in the 300 mg dose group
• Limitations of the study include the small sample size and the lack of comparator group