A Phase 1 Trial of Regorafenib in Advanced Myeloid Malignancies

Angiogenesis is increasingly known to play a role in pathogenesis of hematologic malignancies, including myeloid neoplasms. Regorafenib is a multikinase inhibitor that targets angiogenic, stromal and oncogenic kinases including VEGF- 1, 2, 3, TIE-2, PDGFR-β, c-KIT, rRET, RAF-1, FGFR-1, BRAF and p38 MAP kinase. As a result of regorafenib’s broad inhibition of kinases and its effects on angiogenesis, this drug has the potential to overcome the limitations of more selective kinase inhibitors and may be associated with efficacy in various myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). We conducted a single-center, open-label, dose-escalation and expansion phase I trial in patients with relapsed/refractory AML, MPN, or MDS to assess the safety, tolerability, and preliminary efficacy of regorafenib and identify the recommended phase 2 dose (RP2D). A 3+3 dose escalation design was used with 2 planned dose levels (120 mg or 160 mg daily in 28-day cycles), as well as 1 de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. Six patients were enrolled during the dose escalation phase (3 at 120 mg daily followed by 3 at 160 mg daily), with no DLTs, as defined by a Grade >3 toxicity occurring within the first 28 days after initiation of treatment, and unrelated to the myeloid neoplasm. Therefore, the RP2D of regorafenib was identified as 160 mg daily. Ten additional patients were enrolled on this dose during the expansion phase. The median age was 74 (range 36-84), and 13 (81%) patients were male. Diagnoses included 7 AML, 6 MDS, and 3 MPN patients (Table 1). Dose modifications and delays occurred in 5 and 4 patients, respectively. The median duration of treatment was 56 days or 2.5 cycles (range: 5-410 days, 1-15 cycles). Of the 16 patients, the best overall disease response as measured by IWG criteria included partial remission (in 1 patient with AML), stable disease in 12 (2 de novo AML, 2 secondary AML, 3 MPN, and 5 MDS) patients, and progressive disease in 3 (1 MDS and 2 secondary AML) patients. An initial improvement in absolute neutrophil count and/or hemoglobin was observed in the 6 MDS patients, although this did not meet criteria for hematologic improvement by IWG criteria. All patients have discontinued off treatment. The most frequent Grade 3-4 adverse effects (AEs) included liver function test abnormalities (5.1%), fatigue (4.3%),