Press Conference: Phase I trial shows the benefits of OTX015 in treating blood cancer
Dr Esteban Cvitkovic - Oncoethix, Lausanne, Switzerland
Everybody is excited about bromodomain inhibition and basically bromodomain proteins bind to acetylated histones and therefore bring transcription and elongation together, genes get transcribed, among them many oncogenes. The particularity of the bromodomain is that c-MYC super-enhancers and many cancer relevant biologically genes are transcribed through that. OTX015 and all the other bromodomains when binding to the bromodomain 2, 3 or 4 block therefore transcription does not happen. Of course Bradner started all this and there’s three lots above this and he opened the Pandora’s Box and he will be the discussant today at noon and I cannot even pretend to be at that molecular biology level.
But I will talk about our clinical trial. What is original about it is that because of c-MYK being so relevant, super-enhancer being so common, and because of the clonal nature of disease in general, we decided to go to a haematology phase I trial. It also very originally decided that we went to all haematology if you wish but keep the leukaemias and other hematologic malignancies in two parallel cohorts. This drug is bioavailable orally and people take it as 10mg capsules in a fasted state. We are reporting here about the first… whatever happened up to two weeks ago and actually it happened that we have evaluated the first four dose levels up to 80mg exposure, the last dose level at both once a day and twice a day because there was some preclinical pharmacology evidence of exposure related activity being better both in vitro and in vivo, in half-life. We did that side-step to see if schedule manipulation would be better.
These are two parallel cohorts, acute leukaemia on one side, lymphomas, myelomas and the like on the other. They have a different schedule which is all non-stop, for practical reasons 21 days is considered a cycle, in non-leukaemias and two weeks out of three in acute leukaemias. Although we are now going to continue the leukaemias also. We are reporting again up to the first 42 evaluable patients for safety and 35 of them were evaluable for dose limiting toxicity which was standard for most parameters except for hematologic ones where we had to adapt to the fact that in leukaemia you don’t have platelets to start with so that doesn’t count. DLT is really considered deep aplasia for more than six weeks.
Eligibility was also a little specific to it but we really were not selective at all in terms of molecular signature. We only eliminated promyelocytic and plasma cell leukaemias, bone marrow or stem cell transplant within the last three months, radiation to more than 30% of the bone marrow and then we let pretty much everybody in. What is of note is that first we have acute leukaemias that are heavily pretreated. Second, our population is elderly, it’s 70 on average, heavily pretreated, a lot of stem cell transplants, comorbidity, fragility etc. And about molecular profiles that were likely to supposed to be markers we just are counting the beans but not selecting for them. We do have some of that. We had 2 ALLs, 17 AMLs of which half and half are the normal or secondary to myelodysplasia, myeloproliferation or chemotherapy. We had 5 of those that we know that there is genetic stuff related to bromodomain sensitivity. On the non-leukaemia we have 7 diffuse large B-cell lymphomas, other lymphomas, a little bit of everything, and 9 multiple myelomas. Two previous lines in the leukaemias, five previous lines in other hematologic malignancies.
And this is really… the surprise is that despite the fragility, comorbidity, pre-treatment, elderly, all that stuff, the drug is very, very well tolerated with long times of exposure. I did not put up that slide because of the time limitations but basically half of the patients had at least three cycles and we have five or six patients ongoing with six months of non-stop treatment. So having these kinds of adverse events in that kind of population is remarkable. Of note, thrombocytopenia, the denominator is only non-leukaemias and actually when we did BID it was to increase the Cmin, the trough concentration. We did achieve that, we doubled it. But this is where the only DLTs show that which is thrombocytopenia. Thrombocytopenia is very peculiar because as any other adverse events we stopped the drug and within three days or four everything starts getting back to normal. So every adverse event you see there is reversible upon discontinuation. We had absolutely no cumulative toxicity observed yet. So hyperglycaemia we saw in people that already had diabetes but it was really nothing to write home about. Only one person became insulin dependent for three or four days and most of the others just had to increase a little bit the metformin or change their regimen.
So tolerance is excellent but we do have dose limiting toxicity with a twice daily schedule in high risk or bone marrow in non-leukaemic patients. We therefore went back to QD and we are actively recruiting at the 120mg daily. So this is where we are now and the patients are way too early.
This is the second notable thing, that although we were optimistic, we would not be oncologists otherwise, we did see 7 patients with able to sell to anybody meaningful prolonged clinical activity. 3 of them qualified as formal responses, one of them is still ongoing at 7½ months of continuous treatment, AML. The other one lasted 5 months, was in complete remission when he contemplated recovery and the third one is bad news. The LCBL is a patient that was really very sick, for four months had to stay blah, blah, blah, the crying story and she got better within a week and she’s fine. Seven cycles later on performance set to zero with a very good quality PR.
We also had 4 that although do not qualify for the response thing, there was clearly benefit and they were a couple of, again, acute leukaemias and a couple of indolent lymphomas. One of them, the lymphomas, is ongoing at ten cycles, that means 7½ months, and both of them had symptoms or refractory symptoms like itching with sustained minors, way over five cycles. The other leukaemias progressed after 5 and 6 but they had bone marrow blast decrease etc. etc., they just never recovered peripheral hematologic parameter normality. And there is a couple of … and their BK is a little detailed. We do have proportionality in all parameters; with the BID we got a higher trough concentration, there was variability in the BID schedule. And I mapped the clinical response, the clinical benefit, against AUC; it actually comes even straighter with Cmax.
So it looks like BID and trough concentration are linked to this thrombopenia, it looks that there is dose dependency in the likelihood of response. I remind you that this drug has a continuous sensitivity over a wide variety of malignancies including most hematologic and a lot of solid tumours and paediatrics. So the conclusion is that it’s an orally available drug and excellent tolerance up to 80mg daily. For a few leukaemia patients no DLT was observed, MTD not reached, DLT is thrombocytopenia. MTD is not reached at 80mg but exceeded 40, we are exploring 120. And we have early evidence of meaningful clinical activity in several AML and lymphoma patients with a wide variety of molecular signatures. What we are planning to do next in the upcoming year is maybe within a month or so, because we are pretty damn close to the MTD definition, to get expansion cohorts going in selected hematologics. We would start doing, especially because of the elderly patient profile, probably combination trials in early or lightly pre-treated acute leukaemia in the elderly which for the most part go untreated these days or a little bit of subcutaneous something or other and prayer. And we are going to do the same thing we did in haematology in selected types of solid tumours, late phase 1b, 2, whatever you want to call it, selected tumours. Because we feel that the different exposure to chemo, the younger population, may tolerate a little more drug.
Thank you everybody that participated in the trial, most important my colleagues who could not be here today.