At the ESMO Congress, Amer Zeidan, MBBS, Associated Professor of Medicine, Yale School of Medicine, New Haven, Connecticut, discusses results from the phase 1b portion of a trial exploring onvansertinib in combination with standard-of-care chemotherapy in acute myeloid leukemia (AML).

Transcript

Hi, my name is Amer Zeidan. I'm an Associate Professor of Medicine in the hematology section at Yale University.

I'm here to talk about my presentation in the ESMO meeting, which is titled, "The Use of Onvansertib," which is a polo-like kinase 1 inhibitor, "in Patients with Refractory/Relapsed Acute Myeloid Leukemia in Combination with Decitabine or Low-dose Cytarabine," which I'm presenting on behalf of my authors.

The background of this is that patients with relapsed and refractory acute myeloid leukemia have very poor outcomes and very limited therapeutic options. Polo-like kinases basically are important checkpoints in the cell cycles. They operate at the G2/M point. They are serine/threonine kinases. Inhibition of them in preclinical models have been shown to result in apoptosis and leukemia cell death.

In fact, there was a first-generation polo-like kinase inhibitor called volasertib that was tested in previous clinical trials, which had a positive phase 2 trial in combination with low-dose cytarabine, but the subsequent phase 3 was negative.

There could be several reasons of that, some related to the long half-life of this agent, which was around 5 days, and lack of specificity, as well as issues related to the dosing and the design of those trials.

The current agent, onvansertib, is a specific polo-like kinase 1 inhibitor. It has a shorter half-life than volasertib with a half-life of around 24 hours. We tested and it was actually shown to have activity in preclinical models. It works by inhibition of the enzyme, as I said, at the G2/M checkpoint.

This has been tested in this ongoing phase 1b trial, in which we are reporting on the dose escalation part of the trial. We combine the drug, which is an orally available agent, by the way, with decitabine or low-dose ara-C.

It's given for the first 5 days. Decitabine is given at the standard 20 mg/m2 dose. Low-dose cytarabine was given at 20 mg/m2 subcutaneously for 10 days. There were 2 parallel arms. The patients could go on either one.

The eligibility criteria for the trial were classical for phase 1 trials. The patients could not have more than 3 lines of therapies. They had to have good kidney and liver function and reasonable performance status.

The dose escalation was a classical 3 + 3 design in which we started with 12 mg/m2 of the onvansertib and escalated by 50% at each subsequent dose level. The end points were classical again for phase 1b trials, where the main end point was a safety and exploratory end points in addition to getting a sense of the efficacy of the combination.

The safety was along the lines of what you expect with single-agent HMA or low-dose cytarabine in patients with acute myeloid leukemia. Mostly were grade 1 and grade 2 toxicities. We didn't see a lot of grade 3 and 4 toxicity.

Most of the toxicities that were severe were hematological, as expected, with some febrile neutropenias. There were only 3 deaths on the trial that were not attributed to be related to onvansertib but rather to be due to progression of disease or bleeding, in 1 patient.

Those safety signals were good. The drug is durable at the tested doses, which were tested up to 60 mg/m2 at the data cutoff we present here, which was June 1st, 2019.

In terms of efficacy with decitabine, this is where the efficacy signal was better than cytarabine. With decitabine, we saw 3 responders out of the 12 patients that were evaluable from the dose levels of 12 mg up to the 40 mg/m2.

Two of those responses were full CRs. One was CRi. Those patients had relapsed/refractory leukemia. They were older gentlemen. The 2 CRs were still ongoing, actually, at the time of the data cutoff.

In the low-dose cytarabine arm, we saw 1 responder who had a CRi, out of the 12 patients. Because of that, actually the cytarabine arm is being discontinued. Subsequent testing is going to be in the decitabine arm of this trial.

Overall, this is an ongoing trial. It's focused currently at the safety. The drug appears to be safe, tolerable at the currently tested doses. As the final recommended phase 2 dose is being finalized, basically the treatment will go to the next phase of the expansion in 32 patients to better understand the efficacy.

An important aspect also to point out is that there is a biomarker that is currently being developed looking at the phosphorylation of downstream target of the polo-like kinase and 50% reduction in this biomarker has been associated with response. Where 3 of the patients who have achieved full responses, CR or CRi, had 50% or more reduction while the 4th patient had a 40% reduction. It seems that this biomarker will be helpful.

Of course, a lot of ongoing work is to optimize it and explore it better, and better understand the efficacy and safety in the subsequent dose expansion of this trial.