2411 - Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Low-Dose Cytarabine or Decitabine in Patients with Relapsed/Refractory Acute Myeloid Leukaemia in Phase 1b

Background

Polo-like Kinase 1 (PLK1) is a serine/threonine kinase and master regulator of G2/M cell-cycle progression. Inhibition of PLK1 causes mitotic arrest and cell death. Onvansertib is an orally active, highly selective PLK1 inhibitor with demonstrated safety and tolerability (phase 1, solid tumors) and demonstrates activity in preclinical AML models as a single agent and in combination with cytarabine. Previous studies indicate the phosphorylation status of TCTP (pTCTP), a direct substrate for phosphorylation by PLK1, is a biomarker for PLK1 inhibition by onvansertib.

Methods

R/R AML patients are treated with onvansertib for 5 days in combination with LDAC or decitabine within 21 to 28-day cycle. Dose escalation is 50% increments with dose limiting toxicity (DLT) evaluated at cycle 1 end. For correlative studies, blood samples were collected on day 1 before (0h) and 3h after treatment and % pTCTP (pTCTP/TCTP) was quantified. Positive target engagement was defined as ≥ 50% decrease in pTCTP/TCTP in 0h vs 3h post-dosing. RNA transcriptome analysis of circulating blasts followed by gene set enrichment analysis (GSEA) was compared between patients with target engagement (TE) vs no target engagement (NTE) pre- and post-dosing (t = 0, 3, 24h).

Results

As of April 1, 2019, 24 pts have completed 1 cycle and in both 1b arms with onvansertib dose escalated from 12, 18, 27, 40 to ongoing 60mg/m². No DLTs in either arm to-date. For decitabine arm (n = 12), 2 CR’s and 1 CRi observed from 6 evaluable pts in the two highest doses (27 and 40 mg/m²). For LDAC arm, 1 CR observed from 3 evaluable pts in highest dose (40 mg/m²). For pTCTP status, 9 out of the 22 evaluable patients (41%) showed a decrease of ≥ 50% in % pTCTP at 3h post-dose with 5 of 9 having ≥50% decrease in BM blasts; TE was observed in all CR/CRi’s from both arms. GSEA analysis of TE vs NTE indicated an existing upregulation of MYC targets in TE pre-dose which decreased within TE patients 3h/24h post-dosing.

Conclusions

Dose escalation phase of study to-date demonstrates safety, tolerability and anti-leukaemic activity at higher doses that is significantly correlated with pTCTP biomarker status.

Clinical trial identification

NCT03303339.

Editorial acknowledgement

Legal entity responsible for the study

Trovagene, Inc.

Funding

Trovagene Oncology.

Disclosure

M. Erlander: Full / Part-time employment: Trovagene. All other authors have declared no conflicts of interest.