Next generation of anti-cancer agents: data from ASCO 2013
Dr Sarah Blagden - Imperial College, London, UK
Hello, my name is Sarah Blagden, I’m a medical oncology consultant and I work at Imperial College in London and I’m Director of the Phase I unit there.
Can you tell us about the exciting new ProTide technology that you have been exploring in the NUC-1031 Phase I study?
A company called NuCana BioMed have developed a technology whereby they attach a ProTide moiety onto a standard form of chemotherapy. They’re starting using nucleoside analogues and the first compound that has reached the clinic is a gemcitabine analogue. The company take a pre-activated version of gemcitabine, attach this moiety to it, and then they’ve demonstrated, and we’ve demonstrated in this clinical trial, that we can improve the uptake of gemcitabine and its activity once it’s in the cells.
What are the main benefits of this new technology to cancer patients and which cancer types will it be targeting?
Well it’s interesting because gemcitabine really is effective in about 10% of cancers. What we’ve discovered with this phase I study is that using this analogue of gemcitabine we can broaden the spectrum of cancers that are responsive to gemcitabine. The reason for that is that in the way that they’ve modified the gemcitabine it works in cancers which naturally are resistant to standard gemcitabine and that’s because it is able to bypass a lot of the resistance mechanisms inherent in those cells.
Please explain the advantages of ProTide versus nucleoside analogues.
Well, for example, if you compare it to gemcitabine, what we’re seeing already in the study is that we’re getting 33 times the concentrations of activated gemcitabine in the cells compared to what we know already from studies using the normal gemcitabine. Because we’re getting less of the toxic degradation product, which we think we’ve got about ten times less of that, we’re seeing less toxicity for the patients, which is a huge advantage.
Can you tell us more about the NUC-1031 Phase I study and the revolutionary findings?
It’s a standard two-part, three by three design. So we started with a dose escalation and we’re presenting data today just when we’ve almost completed the dose escalation part. Following that we’ve got a dose expansion part in which we’ll be doing tumour biopsies and PET scans but this initial part is really just to demonstrate that we can prove the concept through the PK and PD data that we’ve been acquiring. The mix of patients, we’ve put eleven on so far. We have patients with cholangiocarcinoma, pancreatic cancer, ovarian and endometrial cancer and also colorectal cancer, which is a cancer that’s not traditionally associated with being highly sensitive to gemcitabine.
How does the NUC-1031 Phase I study compare to others you are working on at the moment?
Normal phase I studies you generally treat patients for about two cycles until their tumours progress because they have come in, they’re heavily pre-treated and their prognosis is already quite poor. What we’re seeing is patients are coming back for more and more cycles of treatment. One of the patients that we’ve described in the poster is a woman with breast cancer, very heavily pre-treated, whose tumour was advancing through all the other treatments she’d ever had and she’s been on our study for six months with completely stable disease and has actually requested to continue to remain on the study for even longer. She’s the first one that has completed all six cycles and we’ve got other patients following behind her who are also getting to the same point of getting near to six cycles with stable disease, which is really exciting.
The early results sound very promising – tell us more about the potential long-term results from this new treatment?
We’re seeing already that the toxicities are in many ways similar to gemcitabine but we’re seeing them with less intensity. So we’re seeing neutropenia and we’re seeing transient elevation in liver enzymes as you would see with gemcitabine but we’re not seeing some of the other traditional gemcitabine toxicities. We’re not getting the fatigue, the nausea, the skin rash and that’s very exciting.
What are the benefits for physicians and patients?
I think it’s really exciting just from the point of view of gemcitabine but also from the point of view of the other chemotherapeutic agents that they’ll be developing in later years. This is really showing that we can almost target cytotoxic chemotherapies. We are looking at predictive markers but it may well be that ProTided chemotherapy agents will become the new backbones of combination chemotherapy treatments in the future.
What are the next steps for the NUC-1031 Phase I study?
The next step is to finish the expansion cohort of the study and really show properly the clinical outcomes in those patients. We’re already working on combination protocols at the moment, combining it with platinum agents and thinking about taking it forward in some of the cancers which are traditionally responsive to gemcitabine like, for example, ovarian cancer and pancreatic cancer.
How does this new therapy support the growing need for personalised cancer treatments?
Yes, we’re looking at a lot of the diagnostics that would perhaps predict whether patients were resistant to gemcitabine. So in the upcoming expansion cohort we’ll be biopsying patients and looking for Hnt expression and expression of things like cytidine deaminase and cytidine kinase. But I think overall we’re looking at something that’s going to be a very useful backbone to combine with a molecularly targeted agent and with reduced toxicity and better efficacy.
What are the take home messages for researchers and oncologists?
I think the take home message is that it’s an exciting opportunity to look again at standard cytotoxic chemos and finding a way to improve their efficacy and safety for patients.