We’re looking at a class of drugs called checkpoint inhibitors and these are not to be confused with immune checkpoints but checkpoint kinase inhibitors.

What those molecules do is when there’s damage to a cell, checkpoints are activated to pause before replication to give time to make repair of the damages.

So if a chemotherapy causes some damage the natural response is for the cell to pause, repair it and so it can survive.

If you can get rid of those checkpoints or get rid of the pauses then the cells will move towards cell death.

So it’s kind of a way we would consider more of a chemopotentiating agent, something that’s going to try to make a standard or FDA approved agent work better.

Can you tell me, then, about the study that you’ve conducted?

We looked at checkpoint kinase 1 inhibitor GDC-0425.

This is a selective Chk1 inhibitor and we gave it in combination with gemcitabine, which is an FDA approved agent and is commonly used for multiple cancer types.

The goal was to try to make gemcitabine work better in those cancer patients.

And your patients had which sorts of solid tumours?

It was a broad phase I study where we were trying to find the best doses of the two drugs to give together.

We were able to give full dose gemcitabine with the 0425 at 60mg for one day on a day one and day eight schedule, gemcitabine on two 21 days or every three weeks.

We enrolled a broad variety of tumour types within the trial.

Of the 40 patients that were enrolled, 10 of them did have breast cancer and 8 of them were triple negative breast cancer, then 5 of them were lung cancer.

So those were the two most common tumour types that enrolled into the trial.

You’ve given some indication already of the safety of the regimen, what exactly did you find and did you see any efficacy?

From a safety standpoint you’re potentiating the gemcitabine hopefully to make it work better but the main side effects are you potentiate the inherent toxicity of gemcitabine which is marrow suppression or bone marrow suppression.

So when we looked at the toxicity profiles the main grade 3/4 adverse events we saw weren’t marrow suppression but predominantly neutropenia; it occurred in about 40% of patients.

Anaemia and thrombocytopenia were below that in the 10-15% range.

So it does have some probably increased marrow suppression when you add the two drugs together but it was very manageable with either dose reductions or dose modifications to the gemcitabine.

We had no other major safety concerns with the combination and the marrow toxicity is the primary adverse event.

Phase I, of course you’re not looking for efficacy but you found some.

Of the 40 patients we had 8 patients that stayed on trial for more than six months.

This was a phase I study so very advanced solid tumour patients.

Of those 8 patients 3 of them were partial responses, one was in a cancer of unknown primary patient, the second was a melanoma patient that had a p53 mutation and the third was a triple negative breast cancer patient that had a p53 mutation.

p53 mutations may increase the chances of responding to a Chk inhibitor because it also affects that checkpoint or the controls on how the cell goes through cycling.

What do you read into these data that is of potential value to cancer doctors?

I think that we’ve been working hard to find combinations of cytotoxic chemos that patients can stay on for long periods of time without getting too many side effects because the standard drugs work, they’re just hard to stay on over long periods.

Developing a chemopotentiator type molecule, you hopefully don’t get too much additive toxicity so that it would be more like just taking a single agent, gemcitabine, but with better activity.

You can imagine that if we could make gemcitabine more potent, and it is approved and used in so many different settings, that this could be a useful combination.

Can the medical community look forward to potentially a new combination?

I think that this trial created a platform that, yes, you can give a Chk inhibitor with gemcitabine.

The safety profile is not much worse than giving gemcitabine alone so the tolerability for the combination was there.

We also were able to show that we can modulate the targeted Chk so that we could give doses of the drug that are actually meaningful and then we had clinical activity but to understand how much better it is than gemcitabine alone will take bigger and randomised trials.