A Phase I Study of Single-Agent Inotuzumab Ozogamicin in Pediatric CD22-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia: Preliminary Results of the ITCC-059 Study

Abstract

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 <0.01% or <1x10-4. PK samples were measured with validated HPLC/MS/MS methods. 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.

Clinical utilization of blinatumomab and inotuzumab immunotherapy in children with relapsed or refractory B‐acute lymphoblastic leukemia

“…The recent COG AALL1621 phase 2 trial (NCT02981628) studied the efficacy of inotuzumab in 48 uniformly treated children and AYAs in second or greater relapse of B‐ALL; preliminary outcomes show CR rates > 50%, nearly two thirds of whom achieved MRD negativity 21 . Preliminary results of the Dutch ITCC‐059 study also showed remarkable efficacy of inotuzumab in pediatric patients with rrALL with an 80% overall response rate and 79% of responding patients achieving an MRD‐negative CR 22 …”

Updates in the Management of Relapsed and Refractory Acute Lymphoblastic Leukemia: An Urgent Plea for New Treatments Is Being Answered!

“…Subsequent trials have demonstrated efficacy in Ph+ and pediatric R/R B-ALL. 32-34 Interestingly, rates of CR and MRD negativity were similar regardless of duration of prior remission, salvage attempt, and burden of disease. Chemotherapy (mini-hyper-CVD) added to InO also has been studied as a phase II with similar response and MRD negativity rates among responders, 78% and 82%, respectively.…”

How the COG is Approaching the High-Risk Patient with ALL: Incorporation of Immunotherapy into Frontline Treatment

“…19 In a retrospective analysis of outcomes for 51 pediatric patients with R/R B-ALL treated with InO via a compassionate access program, the CR/CRi rate for those patients with overt marrow disease (n = 42) was 67%, of whom 71% had MRD < 0.01%. 20 A European phase I trial for pediatric patients reported an overall response (OR) rate of 80%, 79% of whom had MRD < 0.01%, 21 and a recent COG phase 2 single agent study (AALL1621) of InO for children with multiply R/R B-ALL demonstrated a CR/CRi rate of 58.3% (95% CI 43.2-72.4%) in 48 patients. 22 Of those with MRD reported (n = 26), 65.4% had MRD < 0.01%.…”