A Phase II Study to Determine the Safety and Efficacy of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase (IDO) Enzyme INCB024360 in Patients with Myelodysplastic Syndromes

Introduction:

Recent studies emphasized the role of immune dysregulation and innate immune activation in the pathogenesis of myelodysplastic syndromes (MDS). The expansion of T-regulatory cells, namely effector memory cells (Treg EM), in MDS correlates with worse outcome. The expansion of inflammatory hematopoietic suppressive cells called myeloid-derived suppressor cells (MDSC) is sufficient to perturb hematopoiesis and result in the development of MDS in a mouse model. INCB024360 is an oral inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO) which catalyzes the degradation of tryptophan (Trp) to Kynurenine (Kyn). Increased expression of IDO1 was an independent prognostic variable for survival in patients with acute myeloid leukemia (AML). Preclinical data suggests that IDO1 inhibition by INCB024360 will increase T cell proliferation, and decrease T reg cells and will decrease MDSC suppressive activity. We report the results of a phase II clinical study with laboratory correlatives exploring the potential role of INCB024360 for the treatment of MDS patients.

Methods:

This was a phase II, 2-step design to explore the activity and pharmacodynamics of INCB024360 in previously treated MDS patients. All patients signed informed consent. All patients with WHO defined MDS and AML with a myeloblast percentage between 20-30% (RAEB-t by FAB) were included. All risk categories by international prognostic scoring systems (IPSS) were allowed. The study excluded patients with viral hepatitis, HIV infection, prior solid organ or hematopoietic stem cell transplant or active autoimmune disease. The primary endpoint was overall response rate by the International Working Group criteria (IWG 2006). The secondary endpoints included IDO suppression measured intracellular by flowcytometry, change in Treg EM % with treatment and the percentage of bone marrow MDSC change after treatment with INCB024360 . All patients were treated with 600 mg oral twice a day for 16 weeks unless clear evidence of disease progression or toxicity was evident. Descriptive statistics were used to report baseline characteristics and response rates. The paired t-test was used to compare means. The study was registered at clinicaltrials.gov NCT01822691.

Results:

Between August 2013 and January 2014, 15 patients were enrolled at Moffitt Cancer Center. The median age was 72 years the majority of whom were white (93%) and male gender (80%). Seven patients were RCMD WHO subtype, 3 RAEB-I and RAEB-II each, and 1 RARS and MDS/MPN each. The IPSS risk was low 27% (4), intermediate-1 47% (7) and intermediate-2 27% (4). By the revised IPSS, 5 patients were intermediate risk (33%), 2 (13%) high and very high risk respectively. Two thirds were intermediate-2 or high risk by global MD Anderson risk model. The median number of prior therapies was 3 (2-10) and all patients had prior azacitidine therapy. The best response was stable disease in 12 (80%); 3 (20%) patients experienced disease progression and no hematological improvement was observed. The median duration of follow up was 10 months, median duration on study treatment 3.9 months, and median overall survival was not reached. Two patients progressed to AML. The treatment was relatively well tolerated; no treatment-emergent grade 3/4 adverse events were reported. One patient developed hypothyroidism and adrenal insufficiency (grade 2) and one patient had a low testosterone level. Mean IDO expression measured intracellular in mononuclear bone marrow cells was 39% at baseline compared to 26% after treatment (n=9, p 0.4). Mean BFU-E recovery improved from 72 to 191 colonies/10⁶ (n=5, p value 0.036) and mean CFU-GM from 62 to180 colonies/10⁶ (n=6, p 0.5). The mean MDSC % (CD33Lin-HLA cells) was 29.5% at baseline compared to 27.6% after treatment (n=9, p 0.7) however most patients experienced some reduction in MDSC%. The mean T Reg EM cell % changed from 9.6% at screening to 7.4% at end of treatment. (n=14, p 0.8)

Conclusions:

INCB024360 was relatively well tolerated in MDS patients. At the current dosages tested no significant clinical activity was observed. No significant decrease in intracellular IDO expression was observed. No significant decrease in MDSC and T reg EM as potential mechanism of action were observed.

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