Erica Brivio, Marta Lopez-Yurda, Cormac Ownes, Cristina Díaz de Heredia, Bella Bielorai, Claudia Rossig, Vincent van der Velden, Anneke C.J. Ammerlaan, Inge M. van der Sluis, Monique L. Den Boer, Ying Chen, Barbara Sleight, Benoit Brethon, Karsten Nysom, Jan Stary, Ingrid Øra, Christiane Chen-Santel, Luciana Vinti, Franco Locatelli, and Christian Michel Zwaan more...
Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody linked to calicheamicin, approved for relapsed/refractory (R/R) CD22+ B-cell precursor adult acute lymphoblastic leukemia (BCP-ALL) at starting dose of 1.8 mg/m2/course. A phase I study in pediatric patients (pts) is being performed and sponsored by Erasmus MC in collaboration with Pfizer, registered in the Dutch Trial Registry (NTR57360). Study design: Children aged 1-18 years with R/R CD22+ BCP-ALL (ALL) were included after IRB approval and informed consent was obtained. Key inclusion criteria consisted of M2/M3 marrow and adequate liver and kidney function. The study aimed to determine the recommended phase 2 dose (RP2D) of single agent InO; secondary objectives included safety, response and pharmacokinetics (PK). Dose escalation followed the Rolling-6 design, with dose-limiting toxicity (DLT) evaluation during course 1 and defined as delay in hematological (hem) recovery after D42 in responding pts and grade (gr) ≥3 non-hem toxicities >48 hours (or >7 days for liver tests). DL1 was 1.4 mg/m2 (0.6-0.4-0.4 mg/m2). Overall response rate (ORR) was defined as CR, CRp (ANC >0.5x10.9/l but PLT ≤50x10.9/l) and CRi (ANC ≤0.5x10.9/l and/or PLT ≤50,000/µL). Central minimal residual disease (MRD) analysis by flow cytometry and RQ-PCR was considered negative if In the first cohort, 2 patients at DL2 experienced a DLT per protocol definition, however these toxicities were considered non-dose limiting; both pts achieved CR. An IRB-approved amendment allowed repeating the DL1 and DL2 DLT assessment in a 2nd cohort. Survival analysis used the Kaplan-Meier method. Results are based on a database snapshot on June 22, 2019. Results: 25 pts were enrolled (Jan 2017-Apr 2019), median age 11 years (range 1.7-16.9); 3 (12%) were refractory, 15 (60%) ≥2nd relapsed ALL and 7 (28%) 1st relapse post-HSCT (median 2 prior treatment regimens, range 2-7). Eleven (44%) pts were previously transplanted; median baseline WBC 3.5 x109/L (range 0.2-8.6). In total, 46 courses of InO were administered (median 2/pt, range, 1-4). 23 of 25 treated pts were DLT-evaluable. In the first cohort, 1/6 and 2/5 pts at DL1 and DL2 experienced a DLT per protocol definition (transaminases elevation and no hem. recovery), but considered non-dose limiting. After the IRB-approved amendment, in the 2nd cohort, 0/6 and 1/6 pts in DL1 and DL2 had a DLT (no hem recovery). All 25 pts had at least 1 adverse event (AE) in Course 1 [24 gr 3-4]: 20 pts experienced ≥1 gr 3-4 hem AE, 15 pts a gr 3-4 non-hem AE (13 treatment-related, mainly febrile neutropenia/infections and lab abnormalities). Gr 3-4 transaminases elevation related to InO was seen in 3 pts (12%) and bilirubin in 2 (8%) in Course 1. 2 cases of VODs (gr 3-4) were reported after InO, both after follow-up chemotherapy (including HD-MTX) for R/R disease. None of these pts received any HSCT. After Course 1, 75% of pts responded at DL1 and 85% at DL2; ORR 80% (CR n=15, CRp n=1, CRi n=4). MRD was available in 19/20 responding pts: 15 (79%) reached MRD-negative CR as best response (6/9 at DL1 and 9/10 at DL2). Consolidation treatment with HSCT (n=6) or CAR-T cells (n=2) was given a median time of 61 days (range 23-125) after the last InO dose. None of these pts had been previously transplanted. The median follow-up for responding pts was 13.3 months (mos), median duration of response 8 mos (range 1.1-14.0). EFS was 66.7% (95% CI 47.9-93.0) and 33.4% (95% CI: 16.5 − 67.4), while the OS 63.3% (95% CI: 45.8−87.6) and 38.7% (95% CI: 21.3 - 70.4) at 6 and 12 mos, respectively. During follow-up, at relapse 13 pts had material available and sufficient ALL cells for reliable CD22 analysis: 2/13 showed CD22-negativity. After multiple doses, observed Ino medium maximum concentrations in DL1 (n=9) and DL2 (n=5) were 217 and 246 ng.hr/mL, comparable to the simulated adult concentration 234 ng.hr/mL at 1.8 mg/m2 dose. Conclusions: InO was well tolerated and showed remarkable activity in these heavily pretreated pts. The RP2D was established at 1.8 mg/m2/course (0.8-0.5-0.5 mg/m2), confirming the dose used in adults. Two cases of VOD were recorded after follow-up chemotherapy. The ORR was 80%; 79% of responding pts had MRD-negative CR, with 40% of pts being alive after 1 year of follow-up. A phase II single agent study in R/R pediatric ALL is ongoing and a Phase 1 of InO in combination with chemotherapy will start soon. Disclosures Díaz de Heredia: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rossig:Amgen, Celgene,EUSA Pharma, Genetech, Novartis, Roche: Other: advisory board; BMS, Pfizer, Roche: Other: speaker honoraria. van der Velden:Amgen: Honoraria, Research Funding; Jansen: Research Funding; BD Biosciences: Research Funding. van der Sluis:medac: Consultancy; jazz farmaceuticals: Consultancy. Chen:Pfizer Inc.: Employment. Sleight:Pfizer: Employment, Equity Ownership. Nysom:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Teaching and lectures. Øra:Bayer: Membership on an entity's Board of Directors or advisory committees. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zwaan:Novartis: Consultancy; Janssen: Consultancy; Jazz pharmaceuticals: Other: Travel support; Daiichi Sankyo: Consultancy; Servier: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Roche: Consultancy; Incyte: Consultancy. more...