Advances in myeloid disease from ASH 2012 from the Sarah Cannon Research Institute
Dr Michael Savona – Sarah Cannon Research Institute, Nashville, USA
Dr Michael Savona from the Sarah Cannon Research Institute in Nashville talks to ecancer from ASH about some of the novel compounds coming through.
There are several new compounds in the B-cell receptor pathway which have been very exciting for patients, we’ve seen a lot of efficacy. We have several of these PI3 kinase inhibitors in the clinic; we have several B-cell receptor pathway drugs which are not PI3 kinase inhibitors but Bruton’s tyrosine kinase inhibitors or syk inhibitors which also seem to portend a good chance of some efficacy. So we’re very excited about that. We’re working with several different drugs that modify the epigenetics of the tumour cell and we’re excited about those drugs in MDS and AML. We’re also looking at a variety of other novel compounds which work to alter the biochemistry and the bioenergetics of tumour cells.
Tell us more about current research in AML.
It is a very interesting time to take care of patients with AML because there are a lot of drugs that look very promising to take care of these patients’ stem cell pathway inhibitors. The stem cell pathways are essential for embryogenesis; when you’re an adult those stem cell pathways shut down and cancer hijacks those pathways again. It seems that these stem cell pathway inhibitors seem to alter that pro-cancer growth pattern and we’re excited about that. It’s a challenge to take care of patients with AML and put them on clinical trials because if the drug is not active, unfortunately they’ll need therapy quickly because their diseases are so aggressive. This makes it a little more challenging to open clinical trials for patients with acute leukaemia but what we’re finding is some of these pathways are hijacked in less aggressive tumours just as equally and we can often test the drugs, find the proper dose in those cancers and then export the idea at a proper dose that will have a greater chance of efficacy in patients with more aggressive disease.
Give an overview of the research you are presenting at ASH 2012: a phase I dose escalation study of split-dose oprozomib (ONX0912) in patients with hematologic malignancies.
The presentation will be about oprozomib, which is a structural analogue to a drug that was recently approved, carfilzomib. It’s an orally bio-available drug that, like carfilzomib, is an irreversible proteasome inhibitor. As you likely know, the proteasome inhibitors are part and parcel and are the cornerstone, really, of treatment for myeloma these days. The exciting thing about carfilzomib is that there doesn’t seem to be the neuropathy seen in the first generation proteasome inhibitors and the idea of offering a drug like carfilzomib to patients that they can take home with a pill is very attractive. That’s where the idea came from the sponsor to come up with an oral formulation of carfilzomib. The drug has been studied in patients with solid tumours and in different doses and different schedules. The maximum tolerated dose has been reached in solid tumour trials and we haven’t yet reached that in the hematologic malignancies trial, which is encouraging. Now the drug does have some gastrointestinal adverse events which we’re seeing at a rate that becomes really unacceptable at higher doses. To meet that head on there has been a new formulation devised of the medicine in tablet form which in preclinical studies seems to have less toxicity in animals and, so far, the first few patients treated have really done fairly well. So we hope to present that data at a later time in 2013.
Efficacy and results so far. Has it been encouraging?
It’s early yet, only nine patients were included in the analysis before the presentation today, given the data cut-off. But of those patients we have two patients who are in partial remission and one of those patients is actually just about to reach a VGPR; the other has a near 80% reduction in the monoclonal protein. We have a patient in minor remission and that patient is also reaching PR. The other thing that’s encouraging about the drug is when it is tolerated patients reach a reduction in their monoclonal protein but then it continues to drop over time. We’ve had patients who have been on the drug for a year and are still getting improvement in their benefit. So that’s a very encouraging finding.
How will these results impact on clinical practice later down the line? What is the take home message?
The phase I trial that we’re currently running is open to patients with all types of hematologic malignancies. As we reach the MTD this trial will expand and will include patients with multiple myeloma and Waldenström’s macroglobulinemia only. Hopefully we’ll see more of the same and we’ll continue to see responses with lower toxicity with the tablet formulation and those responses will hopefully continue over time. As I mentioned, we’ve had patients who have had response at four weeks and continued response at twenty weeks and then continued response, 26, 28 weeks later.