Over-activation of TGF-b signaling is observed in myelodysplastic syndromes and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-b receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of myelodysplastic syndromes (MDS) and acceptable toxicity in phase 1 studies of solid malignancies.
A Phase 2 multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the IPSS-R criteria with hemoglobin ≤10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off.
Ten of 41 evaluable patients (24.4%, 95% CI: 12.4, 40.3) achieved hematologic improvement erythroid response by IWG 2006 criteria. 18/41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. 9/28 (32.1%) of transfusion-dependent patients had hematologic improvement. 18/41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%).
In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block. ClinicalTrials.gov, number NCT02008318.