Randomized Open-Label Study of INCB047986 in Subjects With Primary Myelodysplastic Syndrome (MDS)

A Randomized, Open-Label, 2-Stage Study of INCB047986 Administered Orally to Subjects With Primary Myelodysplastic Syndrome (MDS) Refractory to or Unlikely to Respond to Erythropoiesis-Stimulating Agents (ESAs)

The study design includes a 3-dose randomization phase to determine effective doses of INCB047986 in patients with myelodysplastic syndrome (MDS) who are refractory or unlikely to respond to erythropoiesis-stimulating agents (ESAs) followed by an extension phase.

After 50% of the subjects have completed 16 weeks of treatment (10 subjects in each dose group), a planned interim analysis will be conducted to determine which, if any, dose levels warrant further investigation based on observing at least 3 responses for hematologic improvement in erythrocytes (HI-E) and adequate safety and tolerability.

Subjects who do not meet the response criteria for erythroid improvement may be treated with ESA in combination with INCB047986 for an additional 16 weeks.

The study comprises:

Screening: up to 4 weeks. Treatment Phase 1: at least 16 weeks of INCB047986. Treatment Phase 2: at least 8 and up to 16 weeks of INCB047986 in combination with ESA if failed treatment in Phase 1.

Extension Phase: Subjects receiving benefit from either therapy may continue indefinitely or until the study is terminated.

Follow-Up: 30 (± 7) days after the last dose of INCB047986 is taken.

Inclusion Criteria:

• Subjects 18 years of age or older.

• Subjects must be diagnosed with MDS according to the World Health Organization (WHO) classification for de novo or primary MDS (Vardiman et al 2009).

• Subjects who require RBC transfusions or are either refractory to or unlikely to respond to ESA therapy should meet one of the following criteria:

  • ESA failure as defined by no improvement in Hgb of at least 1.5 g/dL after 8 weeks of at least 40,000 IU per week of EPO (or equivalent).
  • Have a serum erythropoietin (EPO) of ≥ 500 IU and Hgb level < 10.0 g/dL.
  • Transfusion dependence defined as requiring at least 4 units of packed red blood cells (RBCs) for a Hgb of < 9 g/dL over the 8 weeks prior to screening.

• Subjects may not have received hypomethylating agents or immunosuppressive therapy for their MDS prior to this study.

Exclusion Criteria:

• Subjects at high risk for transformation to acute leukemia as evidenced by poor karyotype or peripheral blood blasts > 10%.
• Subjects with severely compromised bone marrow function as evidenced by trilineage cytopenias with anemia (Hgb < 10 g/L, platelets < 100 × 109/L, and absolute neutrophil count (ANC) < 1.8 × 109/L).
• Subjects who harbor the 5q deletion chromosomal aberration.
• Subjects with chronic myelomonocytic leukemia (CMML).
• Women who are pregnant or breastfeeding, and men and women who cannot comply with requirements to avoid fathering a child or becoming pregnant, respectively.
• Subjects with impaired liver function, end stage renal disease on dialysis, or clinically significant concurrent infections requiring therapy.
• Subjects with unstable cardiac function.
• Invasive malignancies over the previous 2 years except treated basal or squamous carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, Stage 1 or 2 treated prostate