First-in-human phase 1 study of TAK-931 for solid tumours

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Published: 2 Jun 2018
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Dr Toshio Shimizu - National Cancer Center Hospital (NCCH), Tokyo, Japan

Dr Shimizu speaks with ecancer at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting about phase I trials for CDC7 inhibitor TAK-931.

He outlines the scheduling of this first-in-human trial, including dosage escalation and de-escalation upon reaching a maximum tolerated dose, and management of adverse events.

Dr Shimizu summarises the pharmacokinetic profile and response rates, and next steps for further trials.

We just reported the results of the TAK-931 first in human phase I trial regarding the background of the CDC7 targeting inhibitor. So our CDC7 is contributing to initiate the DNA replication by phosphorylating the minichromosome maintenance complex 2.  CDC7 is over-expressed in various kinds of tumour and correlated with a poor prognosis. So targeting CDC7 is considered to be one potential therapy [?? 0:30]. CDC7, a recent preclinical study suggests also revealed activation of the CDC7 and the relation of the CDC7 with a poor prognosis.

When it came to the composure of this trial, can you tell us about the patients recruited?

As of November 2017 a total of 25 patients were enrolled into this first in human phase I study. The vast majority of patients were heavily pre-treated, almost for whom no standard therapy was available.

Has any maximum dose been determined?

Yes, in the cohort of the two [?? 1:13] 60mg once daily as continuous daily dosing, two weeks on and one week off, in a 21 day cycle two out of three patients developed isolated grade 4 neutropenia which required prophylactic administration with a colony stimulating factor and antibiotics. Then dose de-escalation was conducted based on the protocol. So up to 50mg once daily, two weeks on and one week off, in a 21 day schedule TAK-931 managed and the safety profile. It was considered 50mg once daily is the maximum tolerated dose and determined to be the recommended phase II dose.

And when it comes to the pharmacodynamics of the drug, has there been any new understanding there?

One of the exploratory secondary objectives included a determination of the pharmacodynamic effect of the TAK-931. Dose dependent inhibition of the phosphorylation of the minichromosome maintenance complex 2, which is called MCM2, which directs substrate to the CDC7 was observed which correlated reasonably well with drug exposure.

Then I suppose next steps – where does this research lead?

Regarding the clinical evidence of the TAK-931, this is the first report. We just reported our results with clinical efficacy because three patients achieved a partial response in the RECIST criteria and four patients stayed on treatment with a durable, prolonged, stable disease which was 8-9 months. For the next step patient selection is a very good important issue for seeking which patients would be the best candidates to treat by this investigational drug.