Phase I study of sapacitabine and seliciclib in patients with advanced solid tumours
Dr Sara Tolaney - Dana Farber Cancer Institute, Boston, USA
We’ve done some work looking at a combination of drugs – sapacitabine in combination with seliciclib. These are two agents that we’ve been testing in patients with advanced solid tumours. Some of our initial work had focussed on looking at really dosing schedules of these two agents. The sapacitabine is an oral nucleoside analogue and it causes double stranded DNA breaks whereas the seliciclib is a CDK2 and CDK9 inhibitor and it results in a decrease in anti-apoptotic proteins and it also diminishes the HR repair machinery.
Can you talk us through some more of the process of the DNA damage from the sapacitabine?
The sapacitabine gets metabolised into this compound called CNDAC. CNDAC gets incorporated into DNA and it causes initially single stranded DNA breaks but then upon further replication it causes double stranded breaks and if these breaks aren’t repaired it results in cell death. So what we have found is that if you have a tumour that is deficient in homologous recombination sapacitabine seems to be a very efficient compound and it seems that the efficacy is probably enhanced by adding the seliciclib because that’s impairing the repair of the DNA damage that was caused by the sapacitabine.
This is something that was being administered sequentially and concomitant to other therapies. Was there any difference between one first and then the other?
We looked at two different dosing schedules, the reason was that there was some preclinical data that suggested if you give sequential therapy it seems to be synergistic whereas if you give concurrent therapy it potentially seemed like it was antagonistic. So we looked at one schedule in which sapacitabine was given twice daily for seven days followed by three days of seliciclib followed by eleven days off in a 21 day cycle. Then we looked at a second schedule which we call an interleaved approach where it’s really alternating dosing, so a patient will get sapacitabine in the morning then they’ll get seliciclib in the evening and it really is trying to imitate a sequential schedule because the half-life of these agents is so short that the drug will mostly be washed out by the time they’re given the second drug. So we looked at both of these schedules in this phase I study.
And what kind of results have you got from that?
Initially when we looked at the sequential dosing schedule we enrolled patients with all solid tumours and it turned out that the responses were seen only in patients who had a BRCA germline mutation. So when the first cohort of the sequential schedule was done the objective response rate was 25% in patients who had a BRCA mutation. Then we decided to limit enrolment to the second schedule, that interleaved approach, to patients who just had a BRCA mutation and in that schedule the objective response rate was 7% so it was slightly lower than with the first schedule.
So using the marker there, BRCA, it’s a very famous mutation, it’s one that’s entered the common parlance. Do you think it does have a function as a future biomarker for developing therapies?
In this particular case because the sapacitabine’s DNA damage is really HR dependent it seems like a biomarker for response to this agent may in fact be having a germline BRCA mutation. That’s where we’re seeing the predominant efficacy which is encouraging because even in the patients who had a germline BRCA mutation many of them had progressed on prior platinum based therapy and several had even progressed on prior PARP inhibition. So these patients were generally heavily pre-treated, many of whom were treated with agents that were trying to take advantage of their HR deficiency. So it’s encouraging that the regimen seemed to have continued activity.
So where next? You mentioned this was a phase I trial, are there any phase II plans?
We just started enrolling to an expansion cohort to this phase I trial where we’re limiting enrolment to patients who have metastatic breast cancer and a germline BRCA mutation. We’re actually mandating biopsies at baseline to really help us understand how the HR machinery is in those patients up front.