Inotuzumab ozogamicin in paediatric CD22-positive r/r acute lymphoblastic leukaemia: results of the ITCC-059 study
Dr Erica Brivio - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
This is an international study that has been developed within the ITCC, which is a European consortium for innovative therapies for children with cancer that has the aim of developing new agents in paediatric age. This study is also developed within the Paediatric Investigational Plan, this means that the data of the study will be used to try to get an approval for the drug for paediatric age. So inotuzumab ozogamicin is already approved for adults and now with this data of the phase I and phase II of the ITCC study we hope that we could get the drug approved by the FDA and EMA essentially.
This study is performed in a clinical research collaboration with Pfizer because, of course, the pharmaceutical company will then provide the data to the FDA and the EMA to get them the drug approved also for paediatric age.
We have 30 sites open to include patients. This is because, of course, the patients are rare because we include only relapsed patients and at second relapse or first relapse after transplant. So we need a lot of sites to get the number of patients needed for the study.
What were the methods of the study?
The protocol is designed with a phase I phase which was already completed last year and published in October this year. With the recommended phase II dose that we established with the phase I, the phase II has started last year and completed now. So we presented the preliminary results of the analysis at ASH and the full analysis will follow.
The phase I was a rolling-6 design, typical for a paediatric studies, and the phase II had a statistical design with promising activity of the drug if the overall response was above 55%. But we largely achieved this endpoint because we had an overall response above 80%.
What were some of the other key findings?
The phase II confirmed the promising and actually great activity of inotuzumab ozogamicin in relapsed ALL patients. The patients could be included if they are CD22 positive, of course. So we achieved an overall response rate of 81% in phase II with the 27 patients evaluable, so 22 patients achieved a complete response of CRi or CRp if the hematologic recovery was not fully achieved at the end of the course one. All the patients that responded responded after course one, achieved a complete remission after course one, and then the MRD negativity was also very high – around 80% after course one. Then if we count the best responses, so also for the patients that went on with the second or third course, the best response, MRD negativity, was 95% among the responding patients. So a very high percentage.
What are you concluding from these results?
We concluded that inotuzumab ozogamicin is a very active drug in inducing a complete remission in the relapsed setting of ALL and also a very deep remission with a high percentage of MRD negativity. Thanks to this [?] induction treatment in cases of relapse, actually 14 patients of the 22 responders could get a transplant after inotuzumab ozogamicin treatment, so a larger percentage of patients could receive consolidation of the remission achieved. Also three additional patients received CAR T instead of a transplant as a consolidation. So it seems a very active and promising agent in inducing remission with some concerns about the toxicity, as already known in the adult setting – about the liver toxicity above all.
In specific patients that want to go on and receive transplant after inotuzumab ozogamicin we have seen that around 30-35% of the patients that have been transplanted after inotuzumab ozogamicin then developed VRD or SOS, so veno-occlusive disease after transplant. This was a bit in contrast with our findings in the phase I but in phase I we had only seven patients transplanted and none of the patients developed VOD. In this phase II we had 14 patients transplanted with five VOD after transplant which is more in line with the adult findings and also other paediatric retrospective data and also data shown by COG. Probably because in this setting we had more patients already transplanted and patients received in some cases also three courses of inotuzumab ozogamicin, four courses, while it’s generally recommended to not give more than two inotuzumab ozogamicin courses if a transplant is then planned.
What could be the clinical implications of the study?
There is already a great interest in inotuzumab ozogamicin in the paediatric setting also for future frontline treatment. But first of all it will be of interest to use, and it is already planned to use, inotuzumab ozogamicin in the setting of the first relapse patients and in particular too in very high risk patients because we know that when relapsed ALL occurs very early after treatment or during treatment then achieving a second remission is difficult. It seems that inotuzumab ozogamicin can be a good solution to achieve remission in a larger proportion of patients.
So currently the ITCC-059 is still open for inclusion and in a cohort of patients where inotuzumab ozogamicin is combined with chemotherapy. First of all it’s in combination now with vincristine and dexamethasone and if it will be found safe then also PEG-asparaginase will be added in the combination. A future plan, or upcoming plan, is to open a new cohort in very high risk first relapse ALL patients, so patients in which relapse occurs very early or patients that have cytogenetic characteristics for high risk disease to see if inotuzumab ozogamicin can help in achieving remission in a higher proportion of patients.