Background: Polo-like Kinase 1 (PLK1), a serine/threonine kinase, is a master regulator of cell-cycle progression and overexpressed in numerous cancer types including AML. In a randomized phase 2 study, a pan-PLK inhibitor, volasertib, administered IV to patients (pts) with newly diagnosed AML in combination with LDAC showed a statistically significant survival advantage compared to LDAC alone, however a subsequent phase 3 study did not reach significance. Unfavorable features of volasertib may have contributed to this outcome: a long half-life (~5 days), lack of specificity and the safety of the dosing regimen. PCM-075 is a third generation, orally active and highly selective PLK1 inhibitor with a ~24-hour half-life that demonstrates activity in preclinical AML models both as a single agent and in combination with LDAC. It is also safe and well tolerated as shown by a phase 1 trial in pts with solid tumors (Weiss et al 2018 Invest New Drugs 36:85-95). PCM-075 is currently being evaluated in a phase 1b dose-escalation trial (NCT03303339) for R/R AML in combination with either LDAC or D. The primary objective is to assess safety, PK, and the maximum tolerated dose of these drugs in combination. In addition, potential PD biomarkers for response are being explored.

Methods: Pts are treated with PCM-075 for 5 days in combination with either LDAC (20 mg/m2 SC qd x 10d) or D (20 mg/m2 IV qd x 5d) over a flexible 21 to 28-day cycle. Each arm follows a standard dose escalation design with 50% increments in successive cohorts of 3 pts. Dose limiting toxicity (DLT) is evaluated during the 1st cycle. Blood samples and bone marrow (BM) biopsies are obtained within each treatment cycle for PK profiles, PD and genomic biomarker analyses. Immuno- and genomic profiles are characterized in blood and BM blast cells. Assessment of PLK1 inhibition is determined by changes in phosphorylation status of pTCTP, a PLK1 substrate. Genomic analysis (detection of fusions and mutations) and gene expression analysis (RNA-seq) are being used to identify genetic subtypes and gene expression signatures that may be associated with response to treatment.

Results: As of July 20, 2018, 12 pts (9M, 3F), ages 33-88 (median 66 years) were enrolled in this trial. At the starting dose of 12mg/m2 of PCM-075, 3 pts received LDAC and 4 D. The second cohort (18mg/m2) enrolled 5 pts; 3 received LDAC and 2 received D. The median duration of treatment for all pts was 1 cycle (range 1-4 cycles); 5 pts are still ongoing. Adverse events (AEs) were evaluated for 9 pts based on available data. Events observed in more than one pt included fatigue (4), constipation (2) and nausea (2), and all were grade ≤2. Hyponatremia was reported in 2 patients, grades 1 and 3, respectively. All non-hematologic AEs were reversible and considered treatment-unrelated except for a grade 1 fatigue (1 pt) and grade 1 nausea (1 pt). Serious adverse events were reported for 5 pts as 17 separate events but none were considered treatment-related. The most frequent SAE was febrile neutropenia (3 pts). No treatment-related deaths or DLTs occurred and escalation of dosing is ongoing.

PK profiles of PCM-075 in LDAC and D pts were similar to profiles obtained from pts treated with PCM-075 alone in the previous phase 1 trial, suggesting no drug interaction between PCM-075 with LDAC or D.

To date, PD markers were evaluated in 8 pts. Three pts showed a significant decrease in PLK1 activity via assessment of pTCTP status 3h after treatment that was sustained after 4 daily doses of PCM-075. In these 3 pts, percent circulating blasts were reduced from 33% to 7%, 92% to 24%, and 61% to 4%. BM blasts in these pts were reduced from 75% to 60% (cycle 2), 96% to 40% (cycle 2), and 30% to 15% (cycle 1), respectively. Conversely, in pts who did not show decreases greater than 10% in either circulating or BM blasts, PLK1 inhibition was not observed, suggesting a potential correlation between PLK1 inhibition and reduction of blast cells.

Conclusions: The combination of PCM-075 with either LDAC or D demonstrated safety and tolerability in the first two dose cohorts of patients with R/R AML, and further dose escalation is ongoing. Evidence of PLK1 inhibition has been observed and this appears to be correlated with systemic blast reduction. Additional clinical activity, genomic and gene expression analysis of other biomarkers associated with PLK1 inhibition and response to treatment will be provided from expanded and escalated dosing cohorts.


Zeidan:Abbvie: Consultancy; Novartis: Consultancy; Ariad: Consultancy, Speakers Bureau; Agios: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Incyte: Employment; Pfizer: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Spira:BMS: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; ADC Therapeutics: Research Funding; Roche: Consultancy. Patel:Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; France Foundation: Honoraria. Ridinger:Trovagene: Employment. Silberman:Trovagene: Consultancy. Erlander:Trovagene: Employment. Cortes:Novartis: Consultancy, Research Funding; Arog: Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.